Substituted naphthyl p38α mitogen-activated protein kinase inhibitors

ABSTRACT

Substituted naphthyl p38α mitogen-activated protein kinase inhibitors, pharmaceutical compositions thereof, and the use of the substituted naphthyl p38α mitogen-activated protein kinase inhibitors and pharmaceutical compositions thereof for treating diseases are disclosed.

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 63/164,664 filed on Mar. 23, 2021, which isincorporated by reference in its entirety.

FIELD

The present disclosure relates to substituted naphthyl p38αmitogen-activated protein kinase inhibitors, pharmaceutical compositionsthereof, and the use of the substituted naphthyl p38α mitogen-activatedprotein kinase inhibitors and pharmaceutical compositions thereof fortreating diseases.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. The ASCII copy, created on Mar. 21, 2022, isnamed 67LZ-000610PC-349166_SL.txt and is 755 bytes in size.

BACKGROUND

Mitogen-activated protein kinases (MAPKs) are serine/threonine proteinkinases that process and regulate cellular properties in response to awide range of extracellular stimuli. These enzymes phosphorylate the OHgroup of serine or threonine in proteins and play important roles in theregulation of cell proliferation, differentiation, survival andapoptosis. In mammalian cells, several distinct MAPKs have beenidentified, including p38 MAPK.

p38 MAPKs are a class of MAPKs responsive to stress stimuli such asinflammatory cytokines and reactive oxygen species (ROS) and is involvedin a wide range of signaling pathways that stimulate differentbiological functions. For example, p38 MAPK has been found to play anessential role in the regulation of pro-inflammatory signaling networksand in the biosynthesis of cytokines, including tumor necrosis factor-α(TNF-α) and interleukin-1β (IL-1β) in immune cells

Studies have shown that p38 MAPKs contribute to the pathogenesis ofchronic inflammation, leading to preclinical or clinical trials for theapplication of p38 MAPK inhibitors in inflammatory diseases such asrheumatoid arthritis and asthma.

p38 MAPKs comprise four isoforms (α, β, γ and δ). p38α MAPK was thefirst isoform of p38 MAPK to be identified and was first recognized as astress-induced kinase that can be activated by lipopolysaccharide (LPS)and inflammatory cytokines. Inhibition of p38 MAPK has been shown toeffectively alleviate the symptoms of inflammatory diseases such asrheumatoid arthritis, cardiovascular disease, and inflammatory pain.

Many p38 MAPK catalytic inhibitors are poorly effective and causetoxicity possibly due to activity against non-inflammatory p38 and lossof p38α-dependent counterregulatory responses. p38α MAPK inhibitors thatcan selectively block certain p38α MAPK functions and preserve criticalcounterregulatory and homeostatic functions with application for thetreatment of inflammatory and oncologic diseases are desired.

SUMMARY

According to the present invention, a compound has the structure ofFormula (6):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   R¹ is selected from C₁₋₄ alkanediyl, C₁₋₄ heteroalkanediyl,        substituted C₁₋₄ alkanediyl, and substituted C₁₋₄        heteroalkanediyl;    -   R² is substituted C₅₋₈ heterocycloalkyl;    -   R³ is selected from —C(═O)— and —S(═O)₂—; and

R⁴ is selected from —N(R⁵)₂ wherein each R⁵ is independently selectedfrom hydrogen and C₁₋₄ alkyl.

According to the present invention pharmaceutical compositions comprisea compound according to the present invention or a pharmaceuticallyacceptable salt thereof.

According to the present invention, methods of treating a disease in apatient comprise administering to a patient in need of such treatment atherapeutically effective amount of a compound according to the presentinvention or a pharmaceutically acceptable salt thereof, wherein thedisease is treated by inhibiting the p38α MAPK receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings described herein are for illustration purposes only. Thedrawings are not intended to limit the scope of the present disclosure.

FIG. 1 shows the cell viability (black) and IC₅₀ (red) curves for aSARS-CoV-2 cell line treated with Compound (4).

FIG. 2 shows the cell viability (black) and IC₅₀ (red) curves for aSARS-CoV-2 cell line treated with Compound (1).

FIG. 3 shows the cell viability (black) and IC₅₀ (red) curves for aSARS-CoV-2 cell line treated with Compound (2).

DETAILED DESCRIPTION

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a moiety or substituent. For example,—CONH₂ is attached through the carbon atom.

“Alkyl” refers to a saturated, branched, or straight-chain, monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene, or alkyne. Examples ofalkyl groups include methyl; ethyls such as ethanyl, ethenyl, andethynyl; propyls such as propan-1-yl, propan-2-yl, prop-1-en-1-yl,prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-1-yn-1-yl, prop-2-yn-1-yl,etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl,2-methyl-propan-2-yl, but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, but-1-yn-1-yl, but-1-yn-3-yl,but-3-yn-1-yl, etc.; and the like. The term “alkyl” includes groupshaving any degree or level of saturation, i.e., groups havingexclusively carbon-carbon single bonds, groups having one or morecarbon-carbon double bonds, groups having one or more carbon-carbontriple bonds, and groups having combinations of carbon-carbon single,double, and triple bonds. Where a specific level of saturation isintended, the terms alkanyl, alkenyl, and alkynyl are used. An alkylgroup can be C₁₋₆ alkyl, C₁₋₅ alkyl, C₁₋₄ alkyl, C₁₋₃ alkyl, ethyl ormethyl.

“Alkoxy” refers to a radical —OR where R is alkyl as defined herein.Examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.An alkoxy group can be C₁₋₆ alkoxy, C₁₋₅ alkoxy, C₁₋₄ alkoxy, C₁₋₃alkoxy, ethoxy or methoxy.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Aryl encompasses 5- and 6-membered carbocyclic aromatic rings,for example, benzene; bicyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, naphthalene, indane, andtetralin; and tricyclic ring systems wherein at least one ring iscarbocyclic and aromatic, for example, fluorene. Aryl encompassesmultiple ring systems having at least one carbocyclic aromatic ringfused to at least one carbocyclic aromatic ring, cycloalkyl ring, orheterocycloalkyl ring. For example, aryl includes a phenyl ring fused toa 5- to 7-membered heterocycloalkyl ring containing one or moreheteroatoms selected from N, O, and S. For such fused, bicyclic ringsystems wherein only one of the rings is a carbocyclic aromatic ring,the radical carbon atom may be at the carbocyclic aromatic ring or atthe heterocycloalkyl ring. Examples of aryl groups include groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene, and the like. An aryl group can be C₆₋₁₀ aryl, C₆₋₉aryl, C₆₋₈ aryl, or phenyl. Aryl, however, does not encompass or overlapin any way with heteroaryl, separately defined herein.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom is replaced with an aryl group.Examples of arylalkyl groups include benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl, or arylalkynyl is used. An arylalkyl group canbe C₇₋₁₆ arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is C₁₋₆ and the aryl moiety is C₆₋₁₀. An arylalkyl groupcan be C₇₋₁₆ arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety ofthe arylalkyl group is C₁₋₆ and the aryl moiety is C₆₋₁₀. An arylalkylgroup can be C₇₋₉ arylalkyl, where the alkyl moiety can be C₁₋₃ alkyland the aryl moiety can be phenyl. An arylalkyl group can be C₇₋₁₆arylalkyl, C₇₋₁₄ arylalkyl, C₇₋₁₂ arylalkyl, C₇₋₁₀ arylalkyl, C₇₋₈arylalkyl, or benzyl.

“Bioavailability” refers to the rate and amount of a drug that reachesthe systemic circulation of a patient following administration of thedrug or prodrug thereof to the patient and can be determined byevaluating, for example, the plasma or blood concentration-versus-timeprofile for a drug. Parameters useful in characterizing a plasma orblood concentration-versus-time curve include the area under the curve(AUC), the time to maximum concentration (T_(max)), and the maximum drugconcentration (C_(max)), where C_(max) is the maximum concentration of adrug in the plasma or blood of a patient following administration of adose of the drug or form of drug to the patient, and T_(max) is the timeto the maximum concentration (C_(max)) of a drug in the plasma or bloodof a patient following administration of a dose of the drug or form ofdrug to the patient.

“Oral bioavailability” (F %) refers to the fraction of an oraladministered drug that reaches systemic circulation. Oralbioavailability is a product of fraction absorbed, fraction escapinggut-wall elimination, and fraction escaping hepatic elimination; and thefactors that influence bioavailability can be divided intophysiological, physicochemical, and biopharmaceutical factors.

“Compounds” and moieties disclosed herein include any specific compoundswithin the disclosed formula. Compounds may be identified either bychemical structure and/or by chemical name. Compounds are named usingthe ChemBioDraw Professional 17.1.0.105 (9) (CambridgeSoft, Cambridge,Mass.) nomenclature program. When the chemical structure and chemicalname conflict, the chemical structure is determinative of the identityof the compound. The compounds described herein may comprise one or morestereogenic centers and/or double bonds and therefore may exist asstereoisomers such as double-bond isomers (i.e., geometric isomers),enantiomers, diastereomers, or atropisomers. Accordingly, any chemicalstructures within the scope of the specification depicted, in whole orin part, with a relative configuration encompass all possibleenantiomers and stereoisomers of the illustrated compounds including thestereoisomerically pure form (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and enantiomeric and stereoisomericmixtures. Enantiomeric and stereoisomeric mixtures may be resolved intotheir component enantiomers or stereoisomers using separation techniquesor chiral synthesis techniques well known to the skilled in the art.

Compounds and moieties disclosed herein include optical isomers ofcompounds and moieties, racemates thereof, and other mixtures thereof.In such embodiments, the single enantiomers or diastereomers may beobtained by asymmetric synthesis or by resolution of the racemates.Resolution of the racemates may be accomplished, for example, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiralhigh-pressure liquid chromatography (HPLC) column with chiral stationaryphases. In addition, compounds include (Z)- and (E)-forms (or cis- andtrans-forms) of compounds with double bonds either as single geometricisomers or mixtures thereof.

Compounds and moieties may also exist in several tautomeric formsincluding the enol form, the keto form, and mixtures thereof.Accordingly, the chemical structures depicted herein encompass allpossible tautomeric forms of the illustrated compounds. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms. Certain compounds may exist in multiple crystalline,co-crystalline, or amorphous forms. Compounds include pharmaceuticallyacceptable salts thereof, or pharmaceutically acceptable solvates of thefree acid form of any of the foregoing, as well as crystalline forms ofany of the foregoing.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylradical. A cycloalkyl group can be C₃₋₈ cycloalkyl, C₃₋₅ cycloalkyl,C₅₋₆ cycloalkyl, cyclopropyl, cyclopentyl, or cyclohexyl. A cycloalkylcan be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloseptyl, and cyclooctyl.

“Cycloalkylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom is replaced with a cycloalkylgroup as defined herein. Where specific alkyl moieties are intended, thenomenclature cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl isused. A cycloalkylalkyl group can be C₄₋₃₀ cycloalkylalkyl, e.g., thealkanyl, alkenyl, or alkynyl moiety of the cycloalkylalkyl group isC₁₋₁₀ and the cycloalkyl moiety of the cycloalkylalkyl moiety is C₃₋₂₀.A cycloalkylalkyl group can be C₄₋₂₀ cycloalkylalkyl, e.g., the alkanyl,alkenyl, or alkynyl moiety of the cycloalkylalkyl group is C₁₋₈ and thecycloalkyl moiety of the cycloalkylalkyl group is C₃₋₁₂. Acycloalkylalkyl can be C₄₋₉ cycloalkylalkyl, wherein the alkyl moiety ofthe cycloalkylalkyl group is C₁₋₃ alkyl, and the cycloalkyl moiety ofthe cycloalkylalkyl group is C₃₋₆ cycloalkyl. A cycloalkylalkyl groupcan be C₄₋₁₂ cycloalkylalkyl, C₄₋₁₀ cycloalkylalkyl, C₄₋₈cycloalkylalkyl, and C₄₋₆ cycloalkylalkyl. A cycloalkylalkyl group canbe cyclopropylmethyl (—CH₂-cyclo-C₃H₅), cyclopentylmethyl(—CH₂-cyclo-C₅H₉), or cyclohexylmethyl (—CH₂-cyclo-C₆H₁₁). Acycloalkylalkyl group can be cyclopropylethenyl (—CH═CH-cyclo-C₃H₅),cyclopentylethynyl (—C≡C-cyclo-C₅H₉), or the like.

“Cycloalkylheteroalkyl” by itself or as part of another substituentrefers to a heteroalkyl group in which one or more of the carbon atoms(and certain associated hydrogen atoms) of an alkyl group areindependently replaced with the same or different heteroatomic group orgroups and in which one of the hydrogen atoms bonded to a carbon atom isreplaced with a cycloalkyl group. Where specific alkyl moieties areintended, the nomenclature cycloalkylheteroalkanyl,cycloalkylheteroalkenyl, and cycloalkylheteroalkynyl is used. In acycloalkylheteroalkyl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, —SO₂—, —Si—, —B—, or the heteroatomic groupcan be selected from —O— and —NH—, or the heteroatomic group is —O— or—NH—.

“Cycloalkyloxy” refers to a radical —OR where R is cycloalkyl as definedherein. Examples of cycloalkyloxy groups include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. A cycloalkyloxy groupcan be C₃₋₆ cycloalkyloxy, C₃₋₅ cycloalkyloxy, C₅₋₆ cycloalkyloxy,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

“Disease” refers to a disease, disorder, condition, or symptom of any ofthe foregoing.

“Drug” as defined under 21 U.S.C. § 321(g)(1) means “(A) articlesrecognized in the official United States Pharmacopoeia, officialHomeopathic Pharmacopoeia of the United States, or official NationalFormulary, or any supplement to any of them; and (B) articles intendedfor use in the diagnosis, cure, mitigation, treatment, or prevention ofdisease in man or other animals; and (C) articles (other than food)intended to affect the structure or any function of the body of man orother animals . . . .”.

“Halogen” refers to a fluoro, chloro, bromo, or iodo group.

“Heteroalkoxy” refers to an alkoxy group in which one or more of thecarbon atoms are replaced with a heteroatom. A heteroalkoxy group can beC₁₋₆ heteroalkoxy, C₁₋₅ heteroalkoxy, C₁₋₄ heteroalkoxy, or C₁₋₃heteroalkoxy. In a heteroalkoxy, the heteroatomic group can be selectedfrom —O—, —S—, —NH—, —NR— where R is C₁₋₆ alkyl, —SO—, —SO₂—, —Si—, and—B—, or the heteroatomic group can be selected from —O— and —NH—, or theheteroatomic group is —O— and —NH—. A heteroalkoxy group can be C₁₋₆heteroalkoxy, C₁₋₅ heteroalkoxy, C₁₋₄ heteroalkoxy, or C₁₋₃heteroalkoxy.

“Heteroalkyl” by itself or as part of another substituent refer to analkyl group in which one or more of the carbon atoms (and certainassociated hydrogen atoms) are independently replaced with the same ordifferent heteroatomic group or groups. Examples of heteroatomic groupsinclude —O—, —S—, —Si—, —B—, —NH—, —NR—, —O—O—, —S—S—, ═N—N═, —N═N—,—N═N—NR—, —PR—, —P(O)OR—, —P(O)R—, —POR—, —SO—, —SO₂—, and —Sn(R)₂—,where each R is independently selected from hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₆₋₁₂ aryl, substituted C₆₋₁₂ aryl, C₇₋₁₈arylalkyl, substituted C₇₋₁₈ arylalkyl, C₃₋₇ cycloalkyl, substitutedC₃₋₇ cycloalkyl, C₃₋₇ heterocycloalkyl, substituted C₃₋₇heterocycloalkyl, C₁₋₆ heteroalkyl, substituted C₁₋₆ heteroalkyl, C₆₋₁₂heteroaryl, substituted C₆₋₁₂ heteroaryl, C₇₋₁₈ heteroarylalkyl, andsubstituted C₇₋₁₈ heteroarylalkyl. Each R can be independently selectedfrom hydrogen and C₁₋₃ alkyl. Reference to, for example, a C₁₋₆heteroalkyl, means a C₁₋₆ alkyl group in which at least one of thecarbon atoms (and certain associated hydrogen atoms) is replaced with aheteroatom. For example, C₁₋₆ heteroalkyl includes groups having fivecarbon atoms and one heteroatom, groups having four carbon atoms and twoheteroatoms. In a heteroalkyl, the heteroatomic group can be selectedfrom —O—, —S—, —NH—, —N(—CH₃)—, —SO—, —SO₂—, —Si—, and —B—, or theheteroatomic group can be selected from —O— and —NH—, or theheteroatomic group can be —O— or —NH—. A heteroalkyl group can be C₁₋₆heteroalkyl, C₁₋₅ heteroalkyl, or C₁₋₄ heteroalkyl, or C₁₋₃ heteroalkyl.

“Heteroaryl” by itself or as part of another substituent refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system.Heteroaryl encompasses multiple ring systems having at least oneheteroaromatic ring fused to at least one other ring, which may bearomatic or non-aromatic. For example, heteroaryl encompasses bicyclicrings in which one ring is heteroaromatic and the second ring is aheterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systemswherein only one of the rings contains one or more heteroatoms, theradical carbon may be at the aromatic ring or at the heterocycloalkylring. When the total number of N, S, and O atoms in the heteroaryl groupexceeds one, the heteroatoms may or may not be adjacent to one another.The total number of heteroatoms in the heteroaryl group is not more thantwo. In a heteroaryl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(—CH₃)—, —SO—, —SO₂—, —Si—, and —B—, or the heteroatomicgroup can be selected from —O— and —NH—, or the heteroatomic group canbe —O— or —NH—. A heteroaryl group can be selected from, for example,C₅₋₁₀ heteroaryl, C₅₋₉ heteroaryl, C₅₋₈ heteroaryl, C₅₋₇ heteroaryl,C₅₋₆ heteroaryl, C₅ heteroaryl or C₆ heteroaryl.

Examples of heteroaryl groups include groups derived from acridine,arsindole, carbazole, a-carboline, chromane, chromene, cinnoline, furan,imidazole, indazole, indole, indoline, indolizine, isobenzofuran,isochromene, isoindole, isoindoline, isoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene,thiazolidine, and oxazolidine. A heteroaryl groups can be derived, forexample, from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole, or pyrazine. For example, aheteroaryl can be C₅ heteroaryl and can be selected from furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, or isoxazolyl. Aheteroaryl can be C₆ heteroaryl, and can be selected from pyridinyl,pyrazinyl, pyrimidinyl, and pyridazinyl.

“Heteroarylalkyl” refers to an arylalkyl group in which one of thecarbon atoms (and certain associated hydrogen atoms) is replaced with aheteroatom. A heteroarylalkyl group can be C6-16 heteroarylalkyl, C₆₋₁₄heteroarylalkyl, C₆₋₁₂ heteroarylalkyl, C₆₋₁₀ heteroarylalkyl, C₆₋₈heteroarylalkyl, or C₇ heteroarylalkyl, or C₆ heteroarylalkyl. In aheteroarylalkyl, the heteroatomic group can be selected from —O—, —S—,—NH—, —N(—CH₃)—, —SO—, —SO₂—, —Si—, and —B—, or the heteroatomic groupcan be selected from —O— and —NH—, or the heteroatomic group can be —O—or —NH—.

“Heterobicycloalkyl” refers to a moiety having two heterocycloalkylgroups. A heterobicyclycloalkyl group can be a fused ring or spirocompound.

“Heterocycloalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and certain associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom; or to a parent aromaticring system in which one or more carbon atoms (and certain associatedhydrogen atoms) are independently replaced with the same or differentheteroatom such that the ring system violates the Hückel-rule. Examplesof heteroatoms to replace the carbon atom(s) include N, P, O, S, B, andSi. Examples of heterocycloalkyl groups include groups derived fromepoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, and quinuclidine. Aheterocycloalkyl can be C₅ heterocycloalkyl and is selected frompyrrolidinyl, tetrahydropyranyl, tetrahydrothiophenyl, imidazolidinyl,oxazolidinyl, thiazolidinyl, doxolanyl, and dithiolanyl. Aheterocycloalkyl can be C₆ heterocycloalkyl and can be selected frompiperidinyl, tetrahydropyranyl, piperizinyl, oxazinyl, dithianyl, anddioxanyl. A heterocycloalkyl group can be C₃₋₈ heterocycloalkyl, C₃₋₈heterocycloalkyl, C₃₋₅ heterocycloalkyl, C₅₋₆ heterocycloalkyl, C₅heterocycloalkyl or C₆ heterocycloalkyl. In a heterocycloalkyl, theheteroatomic group can be selected from —O—, —S—, —NH—, —N(—CH₃)—, —SO—,—SO₂—, —Si—, —B—, or the heteroatomic group can be selected from —O— and—NH—, or the heteroatomic group can be —O— or —NH—.

“Heterocycloalkylalkyl” refers to a cycloalkylalkyl group in which oneor more carbon atoms (and certain associated hydrogen atoms) of thecycloalkyl ring are independently replaced with the same or differentheteroatom. A heterocycloalkylalkyl can be C₄₋₁₂ heterocycloalkylalkyl,C₄₋₁₀ heterocycloalkylalkyl, C₄₋₈ heterocycloalkylalkyl, C₄₋₆heterocycloalkylalkyl, C₆₋₇ heterocycloalkylalkyl, or C₆heterocycloalkylalkyl or C₇ heterocycloalkylalkyl. In aheterocycloalkylalkyl, the heteroatomic group can be selected from —O—,—S—, —NH—, —N(CH₃)—, —SO—, —SO₂—, —Si—, —B—, or the heteroatomic groupcan be selected from —O— and —NH—, or the heteroatomic group can be —O—or —NH—.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a cyclic conjugated π (pi) electron systemwith 4n+2 electrons (Hückel rule). Included within the definition of“parent aromatic ring system” are fused ring systems in which one ormore of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for example, fluorene, indane,indene, phenalene, etc. Examples of parent aromatic ring systems includeaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, pentacene,pentalene, pentaphene, perylene, phenalene, phenanthrene, picene,pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene,and the like.

“Hydrates” refers to incorporation of water into to the crystal latticeof a compound described herein, in stoichiometric proportions, resultingin the formation of an adduct. Methods of making hydrates include, butare not limited to, storage in an atmosphere containing water vapor,dosage forms that include water, or routine pharmaceutical processingsteps such as, for example, crystallization (i.e., from water or mixedaqueous solvents), lyophilization, wet granulation, aqueous filmcoating, or spray drying. Hydrates may also be formed, under certaincircumstances, from crystalline solvates upon exposure to water vapor,or upon suspension of the anhydrous material in water. Hydrates may alsocrystallize in more than one form resulting in hydrate polymorphism.

“Parent aromatic ring system” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Examples ofparent aromatic ring systems include aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, and trinaphthalene.

“Parent heteroaromatic ring system” refers to an aromatic ring system inwhich one or more carbon atoms (and any associated hydrogen atoms) areindependently replaced with the same or different heteroatom in such away as to maintain the continuous π-electron system characteristic ofaromatic systems and a number of π-electrons corresponding to the Hückelrule (4n+2). Examples of heteroatoms to replace the carbon atoms includeN, P, O, S, Si, and B. Specifically included within the definition of“parent heteroaromatic ring systems” are fused ring systems in which oneor more of the rings are aromatic and one or more of the rings aresaturated or unsaturated, such as, for example, arsindole, benzodioxan,benzofuran, chromane, chromene, indole, indoline, xanthene, etc.Examples of parent heteroaromatic ring systems include arsindole,carbazole, β-carboline, chromane, chromene, cinnoline, furan, imidazole,indazole, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, isothiazole, isoxazole,naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine,phenanthroline, phenazine, phthalazine, pteridine, purine, pyran,pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, andthiazolidine, oxazolidine.

“Patient” refers to a mammal, for example, a human.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include acid addition salts, formed with inorganic acids andone or more protonable functional groups such as primary, secondary, ortertiary amines within the parent compound. Examples of suitableinorganic acids include hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. A salt can be formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 4-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonicacid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylaceticacid, lauryl sulfuric acid, gluconic acid, glutamic acid,hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, andthe like. A salt can be formed when one or more acidic protons presentin the parent compound are replaced by a metal ion, e.g., an alkalimetal ion, an alkaline earth ion, or an aluminum ion, or combinationsthereof; or coordinates with an organic base such as ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, and the like. Apharmaceutically acceptable salt can be the hydrochloride salt. Apharmaceutically acceptable salt can be the sodium salt. In compoundshaving two or more ionizable groups, a pharmaceutically acceptable saltcan comprise one or more counterions, such as a bi-salt, for example, adihydrochloride salt.

The term “pharmaceutically acceptable salt” includes hydrates and othersolvates, as well as salts in crystalline or non-crystalline form. Wherea particular pharmaceutically acceptable salt is disclosed, it isunderstood that the particular salt (e.g., a hydrochloride salt) is anexample of a salt, and that other salts may be formed using techniquesknown to one of skill in the art. Additionally, one of skill in the artwould be able to convert the pharmaceutically acceptable salt to thecorresponding compound, free base and/or free acid, using techniquesgenerally known in the art.

“Pharmaceutically acceptable vehicle” refers to a pharmaceuticallyacceptable diluent, a pharmaceutically acceptable adjuvant, apharmaceutically acceptable excipient, a pharmaceutically acceptablecarrier, or a combination of any of the foregoing with which a compoundprovided by the present disclosure may be administered to a patient andwhich does not destroy the pharmacological activity thereof and which isnon-toxic when administered in doses sufficient to provide atherapeutically effective amount of the compound.

“Pharmaceutical composition” refers to a compound provided by thepresent disclosure or a pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable vehicle, with which the compoundprovided by the present disclosure or a pharmaceutically acceptable saltthereof is administered to a patient. Pharmaceutically acceptablevehicles are known in the art.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease). In some embodiments, “preventing” or“prevention” refers to reducing symptoms of the disease by administeringa compound provided by the present disclosure in a preventative fashion.The application of a therapeutic agent for preventing or prevention of adisease of disorder is known as ‘prophylaxis.’ Compounds provided by thepresent disclosure can provide superior prophylaxis because of lowerlong-term side effects over long time periods.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical arts,which are known to be innocuous to a patient, such as water or ethanol.A molecular complex of a compound or moiety of a compound and a solventcan be stabilized by non-covalent intra-molecular forces such as, forexample, electrostatic forces, van der Waals forces, or hydrogen bonds.The term “hydrate” refers to a solvate in which the one or more solventmolecules is water.

“Solvates” refers to incorporation of solvents into to the crystallattice of a compound described herein, in stoichiometric proportions,resulting in the formation of an adduct. Methods of making solvatesinclude, for example, storage in an atmosphere containing a solvent,dosage forms that include the solvent, or routine pharmaceuticalprocessing steps such as, for example, crystallization (i.e., fromsolvent or mixed solvents) vapor diffusion. Solvates may also be formed,under certain circumstances, from other crystalline solvates or hydratesupon exposure to the solvent or upon suspension material in solvent.Solvates may crystallize in more than one form resulting in solvatepolymorphism.

“A compound provided by the present disclosure” refers to a compoundencompassed by Formula (6) and pharmaceutically salts thereof. Incertain embodiments, a compound provided by the present disclosure canfurther include a compound encompassed by Formula (6), pharmaceuticallysalts, solvates, hydrates, and/or prodrugs of any of the foregoing.

Compounds provided by the present disclosure also include crystallineand amorphous forms of the compounds, including, for example,polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs(including anhydrates), conformational polymorphs, and amorphous formsof the compounds, as well as mixtures thereof “Crystalline form” and“polymorph” are intended to include all crystalline and amorphous formsof the compound, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms, as well as mixturesthereof, unless a particular crystalline or amorphous form is referredto.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s). Eachsubstituent can be independently selected from deuterio, halogen, —OH,—CN, —CF₃, —OCF₃, ═O, —NO₂, C₁₋₆ alkoxy, C₁₋₆ alkyl, —COOR, —NR₂, and—CONR₂; wherein each R is independently selected from hydrogen and C₁₋₆alkyl. Each substituent can be independently selected from deuterio,halogen, —NH₂, —OH, C₁₋₃ alkoxy, and C₁₋₃ alkyl, trifluoromethoxy, andtrifluoromethyl. Each substituent can be independently selected fromdeuterio, —OH, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, andtrifluoromethoxy. Each substituent can independently be selected fromdeuterio, C₁₋₃ alkyl, ═O, C₁₋₃ alkyl, C₁₋₃ alkoxy, and phenyl. Eachsubstituent can independently be selected from deuterio, —OH, —NH₂, C₁₋₃alkyl, and C₁₋₃ alkoxy.

“Sustained release” refers to release of a compound from a dosage formof a pharmaceutical composition at a rate effective to achieve atherapeutic or prophylactic concentration of the compound or activemetabolite thereof, in the systemic circulation of a patient over aprolonged period of time relative to that achieved by administration ofan immediate release formulation of the same compound by the same routeof administration. In some embodiments, release of a compound occursover a time period of at least about 4 hours, such as at least about 8hours, at least about 12 hours, at least about 16 hours, at least about20 hours, and in some embodiments, at least about 24 hours.

“Treating” or “treatment” of a disease refers to arresting orameliorating a disease or at least one of the clinical symptoms of adisease or disorder, reducing the risk of acquiring a disease or atleast one of the clinical symptoms of a disease, reducing thedevelopment of a disease or at least one of the clinical symptoms of thedisease or reducing the risk of developing a disease or at least one ofthe clinical symptoms of a disease. “Treating” or “treatment” alsorefers to inhibiting the disease, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both, and to inhibiting atleast one physical parameter or manifestation that may or may not bediscernible to the patient. “Treating” or “treatment” also refers todelaying the onset of the disease or delaying the onset of at least oneor more symptoms thereof in a patient who may be exposed to orpredisposed to a disease or disorder even though that patient does notyet experience or display symptoms of the disease.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a patient for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease or symptom thereof. A “therapeuticallyeffective amount” may vary depending, for example, on the compound, thedisease and/or symptoms of the disease, severity of the disease and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. An appropriate amount in any given instance may beascertained by those skilled in the art or capable of determination byroutine experimentation.

“Therapeutically effective dose” refers to a dose that provideseffective treatment of a disease or disorder in a patient. Atherapeutically effective dose may vary from compound to compound, andfrom patient to patient, and may depend upon factors such as thecondition of the patient and the route of delivery. A therapeuticallyeffective dose may be determined in accordance with routinepharmacological procedures known to those skilled in the art.

“Vehicle” refers to a diluent, excipient or carrier with which acompound is administered to a patient. A vehicle can be apharmaceutically acceptable vehicle. Pharmaceutically acceptablevehicles are known in the art.

“Binding affinity” refers to the strength of the binding interactionbetween a single biomolecule and its ligand/binding partner. Bindingaffinity is expressed as the IC₅₀ value. Binding affinity can bedetermined by phage ELISA competition assays.

“Modulate” and “modulation” refer to a change in biological activity fora biological molecule such as, for example, a protein, gene, peptide, orantibody, where such change may relate to an increase in biologicalactivity such as, for example, increased activity, agonism, activation,expression, upregulation, and/or increased expression, or decrease inbiological activity such as, for example, decreased activity,antagonism, suppression, deactivation, downregulation, and/or decreasedexpression, for the biological molecule.

For example, the compounds described herein can modulate such as inhibitp38α MAPK protein. Compounds provided by the preset disclosure canselectively modulate, such as selectively inhibit, p38α MAPK protein ascompared to other MAPK or p38 MAPK proteins. Compounds provided by thepresent disclosure can selectively modulate such as selectively inhibitp38α MAPK protein as compared to other MAPK or p38 MAPK proteins.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

Reference is now made in detail to certain compounds, compositions, andmethods. The disclosed compounds, compositions, and methods are notintended to be limiting of the claims. To the contrary, the claims areintended to cover all alternatives, modifications, and equivalents.

Compounds provided by the present disclosure are selective inhibitors ofthe p38α MAPK protein. Pharmaceutical compositions provided by thepresent disclosure include compounds provided by the present disclosure.Compounds and pharmaceutical compositions provided by the presentdisclosure can be used to treat diseases in which the disease is treatedby inhibiting the p38α MAPK protein.

Catalytic inhibitors of p38α MAPK can block expression ofproinflammatory cytokines and can block other p38α MAPK signalingpathways that are important for establishing and maintaininghomeostasis.

As an alternative to the catalytic inhibitors, the compounds provided bythe present disclosure target the substrate binding groove of p38α MAPK,which extends between two acidic patches, referred to as the CD and EDdomains, of the MAPK receptor and is distinct from the DEFsubstrate-binding pocket. Downstream substrates, upstream activatingkinases, and possibly scaffolding molecules, interact with p38 MAPKthrough these sites. Compounds provided by the present disclosure canselectively bind to p38α MAPK and not p38β, can stabilize endothelialbarrier function in human lung microvascular endothelial cells(HMVECLs), and/or can inhibit lipopolysaccharide (LPS)-inducedproinflammatory gene expression in THP-1 cells.

Compounds provided by the present disclosure include compounds ofFormula (6) in which R² comprises a substituted fused ring, andcompounds of Formula (6) in which R² comprises a substituted monocyclicring. A compound provided by the present disclosure can have thestructure of Formula (6):

or a pharmaceutically acceptable salt thereof, wherein,

R¹ can be selected from C₁₋₄ alkanediyl, C₁₋₄ heteroalkanediyl,substituted C₁₋₄ alkanediyl, and substituted C₁₋₄ heteroalkanediyl;

R² can be substituted C₅₋₁₂ heterocycloalkyl;

R³ can be selected from —C═O and —S(═O)₂; and

R⁴ can be selected from —N(R⁵)₂ wherein each R⁵ can be independentlyselected from hydrogen and C₁₋₄ alkyl.

In a compound of Formula (6), each of the one or more substituents canbe independently selected from, for example, —OH, ═O, —NH₂, —NO₂, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ cycloalkyl, C₆ aryl, C₁₋₆ heteroalkyl, C₁₋₆heteroalkoxy, C₁₋₆ heterocycloalkyl, C₅₋₆ heteroaryl, substituted C₁₋₆alkyl, substituted C₁₋₆ alkoxy, substituted C₁₋₆ cycloalkyl, substitutedC₆ aryl, substituted C₁₋₆ heteroalkyl, C₁₋₆ substituted heteroalkoxy,substituted C₁₋₆ heterocycloalkyl, and substituted C₅₋₆ heteroaryl.

In a compound of Formula (6), each of the one or more substituents canbe independently selected from —OH, ═O, —NH₂, —NO₂, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ heteroalkyl, C₁₋₃ heteroalkoxy, substituted C₁₋₃ alkyl,substituted C₁₋₃ alkoxy, substituted C₁₋₃ heteroalkyl, and substitutedC₁₋₃ heteroalkoxy.

In a compound of Formula (6), each of the one or more substituents canbe independently selected from, for example, —OH, ═O, C₁₋₃ alkyl, andC₁₋₃ alkoxy.

In a compound of Formula (6), each of the one or more substituents canbe ═O.

In a compound of Formula (6), each of the one or more heteroatoms canindependently be selected from N and O.

In a compound of Formula (6), R¹ can be C₁₋₄ alkanediyl.

In a compound of Formula (6), R¹ can be ethanediyl.

In a compound of Formula (6), R¹ can be methanediyl.

In a compound of Formula (6), R² can be substituted C₆ heterocycloalkyl.

In a compound of Formula (6), each of the one or more heteroatoms can beselected from O and N.

In a compound of Formula (6), R² can be 4-morpholinyl.

In a compound of Formula (6), R² can be substituted 4-morpholinyl.

In a compound of Formula (6), R² can be 3-substituted 4-morpholinyl.

In a compound of Formula (6), R² can be C₅ heterocycloalkyl, C₆heterocycloalkyl, C₇ heterocycloalkyl, C₈ heterocycloalkyl, or C₉heterocycloalkyl.

In a compound of Formula (6), R² can be bonded to R¹ through a nitrogenheteroatom of the C₅₋₁₂ heterocycloalkyl moiety.

In a compound of Formula (6), R² can be a monocyclic C₅₋₁₂ heteroalkylring in which a ring nitrogen heteroatom is bonded to R¹.

In a compound of Formula (6), R² can be a monocyclic C₅₋₁₂ heteroalkylring in which a ring nitrogen hetero atom is bonded to R¹ and having atleast one ring oxygen heteroatom.

In a compound of Formula (6), R² can be a monocyclic C₅₋₁₂ heteroalkylring in which a ring nitrogen heteroatom is bonded to R¹ and having atleast one ring oxygen heteroatom, and at least one oxo (═O) substituent.

In a compound of Formula (6), R² can be a bicyclic C₅₋₁₂ heteroalkylring in which a ring nitrogen heteroatom is bonded to R¹.

In a compound of Formula (6), R² can be a bicyclic C₅₋₁₂ heteroalkylring in which a ring nitrogen hetero atom is bonded to R¹ and having atleast one ring oxygen heteroatom.

In a compound of Formula (6), R² can be a bicyclic C₅₋₁₂ heteroalkylring in which a ring nitrogen heteroatom is bonded to R¹ and having atleast one ring oxygen heteroatom, and at least one oxo (═O) substituent.

In a compound of Formula (6), R² can be selected from4λ²-morpholin-3-one, 4λ²-morpholin-2-one, 1,3λ²-oxazinan-4-one,1,3λ²-oxazinan-5-one, 1,3λ²-oxazinan-6-one, 3λ²-oxazolidin-2-one,3λ²-oxazolidin-4-one, and 3λ²-oxazolidin-5-one. [93] In a compound ofFormula (6), each of the one or more substituents can be selected from—OH, ═O, and —N(R⁵)₂, wherein each R⁵ can be independently selected fromhydrogen and C₁₋₃ alkyl.

In a compound of Formula (6), each of the one or more substituents canbe —OH.

In a compound of Formula (6), each of the one or more substituents can═O.

In a compound of Formula (6), each of the one or more substituents canbe —N(R⁵)₂, wherein each R⁵ can be independently selected from hydrogenand C₁₋₃ alkyl.

In a compound of Formula (6), R³ can be selected from C(═O) and S(O)₂.

In a compound of Formula (6), R³ can be C(═O).

In a compound of Formula (6), R³ can be S(O)₂.

In a compound of Formula (6), R⁴ can be bonded to the 3-position, the4-position, the 5-position, the 6-position, or the 7-position of thenaphthyl moiety.

In a compound of Formula (6), R⁴ can be bonded to the 5-position of thenaphthyl moiety.

In a compound of Formula (6),

R¹ can be C₁₋₃ alkanediyl;

R² can be substituted 4-morpholinyl;

R³ can be selected from C(═O) and S(O)₂; and

R⁴ can be selected from —N(R⁵)₂ wherein each R⁵ can be independentlyselected from hydrogen and C₁₋₃ alkyl.

In a compound of Formula (6),

R¹ can be methane-diyl;

R² can be substituted 4-morpholinyl;

R³ can be S(O)₂; and

R⁴ can be —N(R⁵)₂ wherein each R⁵ can be independently selected fromhydrogen and methyl.

In a compound of Formula (6),

R¹ can be methane-diyl;

R² can be substituted 4-morpholinyl;

R³ can be C(═O); and

R⁴ can be —N(R⁵)₂ wherein each R⁵ can be independently selected fromhydrogen and methyl.

In a compound of Formula (6), R² can be 3-substituted 4-morpholinyl.

In a compound of Formula (6), in a moiety of R², the substituent can be═O.

In a compound of Formula (6), R⁴ can be selected from —NH(—CH₃) and—N(—CH₃)₂.

In a compound of Formula (6), R⁴ can be —NH(—CH₃).

In a compound of Formula (6), R⁴ can be —N(—CH₃)₂.

A compound of Formula (6) can be selected from:

-   -   4-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   4-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   4-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   6-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   6-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;        and    -   6-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;    -   or a pharmaceutically acceptable salt of any of the foregoing.

A compound of Formula (6) can be5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(Compound 5), or a pharmaceutically acceptable salt thereof:

A compound of Formula (6) can be5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(2), or a pharmaceutically acceptable salt thereof:

A compound of Formula (6) can be5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(3), or a pharmaceutically acceptable salt thereof:

A compound of Formula (6) can be a solvate, a pharmaceuticallyacceptable salt, or a combination thereof.

In a compound of Formula (6), a pharmaceutically acceptable salt can bethe hydrochloride salt.

A compound of Formula (6) can be a pharmaceutically acceptable salt of acompound of Formula (6), a hydrate thereof, or a solvate of any of theforegoing.

In certain embodiments, a compound provided by the present disclosure isnot a compound of Formula (1)(5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide):

A compound provided by the present disclosure can be a p38 MAPKinhibitor such as a selective p38 MAPK inhibitor and/or a modulator ofp38α MAPK protein activity.

A compound provided by the present disclosure can be a selectiveinhibitor of p38α MAPK. A selective p38α MAPK inhibitor provided by thepresent disclosure has a higher binding affinity (lower IC₅₀) to thetarget pocket of p38α MAPK than to the catalytic binding site of p38αMAPK. A compound provided by the present disclosure can selectivelyinhibit p38α MAPK. The p38α MAPK inhibitor can bind to p38α MAPK nearthe substrate binding groove of p38α MAPK, which extends between twoacidic patches referred to as the CD and ED domains. The binding pocketcan be defined at least by residues R49, H107, L108, and K165 of p38αMAPK. The binding pocket can be defined at least by residues R49, H107,L108, M109, G1 10, Al 57, V158, El 63, L164, and K165 of p38α MAPK. Thebinding pocket and method for determining selective binding to theselective binding pocket is described, for example, in U.S. ApplicationNo. 2020/0331874 A1 and in U.S. Application No. 2019/0151324 A1.

Selective binding of a compound provided by the present disclosure top38α MAPK can be confirmed using complementary technologies. Forexample, a selective p38α MAPK inhibitor can show aconcentration-dependent increase in melting temperature of p38α but notp38P as determined using differential scanning fluorimetry (DSF) todetect ligand-induced protein stabilization. STD-NMR, which measures lowaffinity protein/ligand binding via non-scalar magnetization transferfrom protein to ligand protons, can be used to confirm specific compoundbinding to p38α and localize the interaction to the aromatic rings ofthe binding site. A p38α MAPK inhibitor can cause aconcentration-dependent increase in melting temperature of p38α MAPK.The difference in melting temperature Tm can be measured at a p38α MAPKinhibitor concentration between 1 nM and 1,000 μM such as at aconcentration of 100 μM. For example, the difference in the meltingtemperature can be from 0.1° C. to about 2° C.

A compound provided by the present disclosure can interact with a pocketnear the ED substrate docking site of p38 MAPK.

A compound provided by the present disclosure can bind to p38α MAPK nearthe substrate binding groove of p38α MAPK, which extends between the CDand ED domains.

A compound provided by the present disclosure can inhibit MK2phosphorylation through interaction with p38α MAPK.

A compound provided by the present disclosure can competitively bind top38α MAPK with4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide.

A compound provided by the present disclosure can have a higher bindingaffinity to the p38α MAPK subunit than to the p383 MAPK subunit.

A p38α MAPK inhibitor provided by the present disclosure can have alogP, for example, from −5 to 10, from −3 to 8, from 0 to 5, 0.1 to 3,from 0.1 to 1, from 0.5 to 1.5, from 0.75 to 2, from 1 to 2.5, or from1.75 to 3. LogP is a measure of drug solubility and is defined as thelogarithm of the octanol/water partition coefficient of the drug.

Phosphorylation of MK2 can involve binding to the ED site adjacent tothe target pocket in p38α MAPK. The target pocket can be defined byamino acids R49, H107, L108, and K165 in p38α MAPK. The target pocketcan be defined by amino acids selected from R49, H107, L108, M109, Gl10, Al 57, V158, El 63, L164, and K165 in p38α MAPK. The target pocketcan be defined by the amino acids R49, H107, L108, M109, Gl 10, Al 57,V158, El 63, L164, and K165 in p38α MAPK.

p38α MAPK inhibitors provided by the present disclosure can at leastpartially inhibit MK2 phosphorylation. For example, Western blotting canbe used to measure inhibition of MK2 phosphorylation inanisomycin-stimulated HeLa cells by a compound provided by the presentdisclosure.

A p38α MAPK inhibitor provided by the present disclosure can stabilizean endothelial or epithelial barrier function. Endothelial barrierpermeability can be measured by separate or combined exposure to TNFaand hyperthermia, followed by measurement of permeability for 10 kDadextran. For example, endothelial barrier stabilization can be assessedby pretreating with a compound provided by the present disclosure,preceded and followed by permeability measurements, where stabilizationcan be expressed as a % reduction in the before and after pretreatmentpermeability increase. A permeability increase caused by 10 kDa dextrancan be reduced by between 5% to more than 100% such as, for example, bygreater than 5%, greater than 10%, greater than 20%, greeter than 40%,greater than 60%, greater than 80%, or greater than 100%.

A p38α MAPK inhibitor provided by the present disclosure can modulateTNFα-induced gene expression in human lung microvascular endothelialcells (HMVECLs) as determined using, for example, RNASeq. For example,HMVECLs can be pretreated for a period of time with a p38α MAPKinhibitor at an appropriate concentration and then stimulated with TNFafor a period of time. A p38α MAPK inhibitor provided by the presentdisclosure can inhibit genes such as PRRG4, TSLP, CCLI 7, EXOC3L4, MMP9,IDOI, CXCL1O, CD200, SLCI5A3, VDR, ILIB, GPR88, CD207, TCHH, HAS3,GBPIPI, MUC4, ELOVL7, CXCL11, GBP4, PLAIA, and/or CXCL5.

The effects of a p38α MAPK inhibitor on inflammatory cytokine expressioncan be determined by pretreating PMA-differentiated THPI cells with ap38α MAPK inhibitor, then stimulating with LPS, and harvesting RNA aperiod of time later for analysis by PCR-based cytokine array. A p38αMAPK inhibitor can inhibit expression of various genes, such as IL-IA,IL-8, TNFSF8, CXCL5, CCL7, CCLI 7, TNFSF9, IL-IB, CXCLI, TNFSFIS, CCL5,CCL4, CCL20, CXCL2, TNF, or BMP6. A p38α MAPK inhibitor can inhibitexpression of Smad3, which drives differentiation of Foxp3 T regulatorycells and suppresses interferon-y. Inflammation reduction can bemeasured by comparing the fold change mRNA levels with unstimulatedPMA-differentiated THPI cells at various concentrations of p38α MAPKinhibitor.

Certain compounds of Formula (6) can be metabolites of a correspondingcompound N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide havingan amine substituent on the naphthyl moiety. For example, a compound ofFormula (2)(5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;Compound 2) and a compound of Formula (3)(5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;Compound 3) can be metabolites of compound (4)(5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide;Compound (4)):

Following administration of compound (4) to a subject, compound (4) canbe metabolized in vivo to provide a compound of Formula (3), a compoundof Formula (2), and a compound of Formula (1)(5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide(Compound 1)):

Compounds of Formula (6) can be synthesized using methods known in theart.

For example, (4-aminophenyl)methanol (A) can be reacted with Boc₂O inCH₂Cl₂ to provide the Boc-protected compound teat-butyl(4-(hydroxymethyl)phenyl)carbamate (B). The Boc-protected intermediate(B) can be reacted with PDC in CH₂Cl₂ to provide teat-butyl(4-acetylphenyl)carbamate (C). Intermediate (C) can be reacted with asuitable substituted morpholine in the presence of NaBH(OAc)₂ in anorganic solvent such as 1,2-dichloroethane (DCE) to provide thecorresponding substituted tent-butyl(4-(morpholinomethyl)phenyl)carbamate (D). Intermediate (D) can bedeprotected in the presence of 4M HCl in methanol to provide thecorresponding substituted 4-(morpholinomethyl)aniline dihydrochloridesalt (E). The salt (E) can be reacted with a suitable substitutedS-(naphthalen-1-yl) chlorothioate (F) in the presence ofN,N-diisopropylethylamine (DIPEA) in dimethylformamide (DMF) to providethe corresponding compound of Formula (6).

Compounds provided by the present disclosure can be incorporated intopharmaceutical compositions to be administered to a patient by anyappropriate route of administration including intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, peroral, sublingual, intracerebral, intravaginal,transdermal, rectal, inhalation, or topical. A pharmaceuticalcomposition provided by the present disclosure can be an injectableformulation. A pharmaceutical composition provided by the presentdisclosure can be injectable intravenous formulation. A pharmaceuticalcomposition provided by the present disclosure can be an oralformulation. An oral formulation can be an oral dosage form. Apharmaceutical composition can be formulated for intravenousadministration or for subcutaneous administration.

A pharmaceutical composition provided by the present disclosure cancomprise a therapeutically effective amount of a compound of Formula (6)together with a suitable amount of one or more pharmaceuticallyacceptable vehicles so as to provide a composition for properadministration to a patient. Suitable pharmaceutical vehicles andmethods of preparing pharmaceutical compositions are described in theart.

Assessing single patient response to therapy and qualifying a patientfor optimal therapy are among the greatest challenges of modernhealthcare and motivate trends in personalized medicine. A compound ofFormula (6) can have target selectivity, for example, for certaincancers and immune cells. A compound of Formula (6) radiolabeled forpositron emission tomography (PET) or Single Photon Emission ComputedTomography (SPECT) can be used to predict the targeting of the treatmentbased on a single-study, case-by-case patient analysis thus excludingpatients that are expected not to benefit from treatment. PET/SPECTscans using a compound of Formula (6), once correlated to theconcentration can provide a three-dimensional distribution map, whichcan then be used for macroscopic dose calculations.

A compound of Formula (6) and/or pharmaceutical composition thereof cangenerally be used in an amount effective to achieve an intended purpose.For use to treat a disease such as cancer, an autoimmune disease or aninflammatory disease, a compound of Formula (6) and/or pharmaceuticalcomposition thereof, may be administered or applied in a therapeuticallyeffective amount.

The amount of a compound of Formula (6) and/or pharmaceuticalcomposition of any of the foregoing that will be effective in thetreatment of a particular disorder or condition will depend in part onthe nature of the disorder or condition, and can be determined bystandard clinical techniques known in the art. In addition, in vitro orin vivo assays may optionally be employed to help identify optimaldosage ranges. The amount of a compound of Formula (6), and/orpharmaceutical composition of any of the foregoing administered willdepend on, among other factors, the patient being treated, the weight ofthe patient, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

A compound of Formula (6) can be assayed in vitro and in vivo, for thedesired therapeutic activity, prior to use in humans. For example, invitro assays may be used to determine whether administration of aspecific compound or a combination of compounds is preferred. Thecompounds can also be demonstrated to be effective and safe using animalmodel systems.

In certain embodiments, a therapeutically effective dose of a compoundof Formula (6) and/or pharmaceutical composition of any of the foregoingwill provide therapeutic benefit without causing substantial toxicity.Toxicity of a compound of Formula (6) and/or pharmaceutical compositionsof any of the foregoing may be determined using standard pharmaceuticalprocedures and may be readily ascertained by the skilled artisan. Thedose ratio between toxic and therapeutic effect is the therapeuticindex. A compound of Formula (6) and/or pharmaceutical composition ofany of the foregoing exhibits a particularly high therapeutic index intreating disease and disorders. A dose of a compound of Formula (6)compound, and/or pharmaceutical composition of any of the foregoing willbe within a range of circulating concentrations that include aneffective dose with minimal toxicity.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be included in a kit that can be used to administer thecompound to a patient for therapeutic purposes. A kit can include apharmaceutical composition comprising a compound provided by the presentdisclosure suitable for administration to a patient and instructions foradministering the pharmaceutical composition to the patient. The kit canbe suitable for treating cancer, for treating an autoimmune disease, orfor treating an inflammatory disease. A kit for use in treating cancer,for treating an autoimmune disease, or for treating an inflammatorydisease can comprise a compound or a pharmaceutical composition providedby the present disclosure, and instructions for administering thecompound to a patient.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be included in a container, pack, or dispenser togetherwith instructions for administration.

Instructions supplied with a kit may be printed and/or supplied, forexample, as an electronic-readable medium, a video cassette, anaudiotape, a flash memory device, or may be published on an internet website or distributed to a patient and/or health care provider as anelectronic communication.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be used to treat a disease in a patient.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be used to treat a disease in which the etiology of thedisease is associated with up-regulation and/or down-regulation of thep38α MAPK protein.

Methods provided by the present disclosure include treating a disease ina patient comprising administering to a patient in need of suchtreatment a therapeutically effective amount of a compound orcomposition provided by the present disclosure, wherein the disease istreated by inhibiting the p38α MAPK protein.

The p38 mitogen-activated protein kinase (MAPK) family of stress- andcytokine-activated kinases are associated with the pathogenesis of manyhuman diseases, including, for example, cancer, rheumatoid arthritis,cardiovascular disease, multiple sclerosis, inflammatory bowel disease,chronic obstructive pulmonary disease (COPD), asthma, acute respiratorydistress syndrome (ARDS), and acute lung injury (ALI). Among the manyimportant biological processes regulated by p38 MAPK, regulation ofendothelial and epithelial barrier function, leukocyte trafficking, andcytokine expression are central to the pathogenesis of acute and chronicinflammatory disorders.

Compounds and pharmaceutical compositions provided by the presentdisclosure may be used for treating cancer in a patient. The cancer canbe, for example, a solid tumor or a metastasis.

Methods provided by the present disclosure include methods of treatingcancer in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a compound orpharmaceutical composition provided by the present disclosure.

Examples of suitable cancers include acoustic neuroma, adenocarcinoma,angiosarcoma, astrocytoma, basal cell carcinoma, bile duct carcinoma,bladder carcinoma, brain cancer, breast cancer, bronchogenic carcinoma,cervical cancer, chordoma, choriocarcinoma, colon cancer, colorectalcancer, craniopharyngioma, cystadenocarcinoma, embryonal carcinoma,endotheliocarcinoma, ependymoma, epithelial carcinoma, esophagealcancer, Ewing's tumor, fibrosarcoma, gastric cancer, glioblastomamultiforme, glioma, head and neck cancer, hemangioblastoma, hepatoma,kidney cancer, leiomyosarcoma, liposarcoma, lung cancer,lymphangioendotheliosarcoma, lymphangiosarcoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, myxosarcoma, nasalcancer, neuroblastoma, oligodendroglioma, oral cancer, osteogenicsarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma,papillary carcinoma, pinealoma, prostate cancer, rhabdomyosarcoma,rectal cancer, renal cell carcinoma, retinoblastoma, sarcoma, sebaceousgland carcinoma, seminoma, skin cancer, squamous cell carcinoma, stomachcancer, sweat gland carcinoma, synovioma, testicular cancer, small celllung carcinoma, throat cancer, uterine cancer, Wilm's tumor, bloodcancer, acute erythroleukemic leukemia, acute lymphoblastic B-cellleukemia, acute lymphoblastic T-cell leukemia, acute lymphoblasticleukemia, acute megakaryoblastic leukemia, acute monoblastic leukemia,acute myeloblastic leukemia, acute myelomonocytic leukemia, acutenonlymphocytic leukemia, acute promyelocytic leukemia, acuteundifferentiated leukemia, chronic lymphocytic leukemia, chronicmyelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chaindisease, and Hodgkin's disease.

Examples of suitable cancers include pancreatic cancer, breast cancer,prostate cancer, lymphoma, skin cancer, colon cancer, melanoma,malignant melanoma, ovarian cancer, brain cancer, primary braincarcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladdercancer, non-small cell lung cancer, head or neck carcinoma, breastcarcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma,Wilms' tumor, cervical carcinoma, testicular carcinoma, bladdercarcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma,prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma,esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma,renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma,malignant pancreatic insulinoma, malignant carcinoid carcinoma,choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervicalhyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocyticleukemia, acute myelogenous leukemia, chronic myelogenous leukemia,chronic granulocytic leukemia, acute granulocytic leukemia, hairy cellleukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma,polycythemia vera, essential thrombocytosis, Hodgkin's disease,non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primarymacroglobulinemia, or retinoblastoma. A cancer can be acoustic neuroma,adenocarcinoma, angiosarcoma, astrocytoma, basal cell carcinoma, bileduct carcinoma, bladder carcinoma, brain cancer, breast cancer,bronchogenic carcinoma, cervical cancer, chordoma, choriocarcinoma,colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,embryonal carcinoma, endotheliocarcinoma, ependymoma, epithelialcarcinoma, esophageal cancer, Ewing's tumor, fibrosarcoma, gastriccancer, glioblastoma multiforme, glioma, head and neck cancer,hemangioblastoma, hepatoma, kidney cancer, leiomyosarcoma, liposarcoma,lung cancer, lymphangioendotheliosarcoma, lymphangiosarcoma, medullarycarcinoma, medulloblastoma, melanoma, meningioma, mesothelioma,myxosarcoma, nasal cancer, neuroblastoma, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinoma, papillary carcinoma, pinealoma, prostate cancer,rhabdomyosarcoma, rectal cancer, renal cell carcinoma, retinoblastoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, squamous cellcarcinoma, stomach cancer, sweat gland carcinoma, synovioma, testicularcancer, small cell lung carcinoma, throat cancer, uterine cancer, Wilmstumor, blood cancer, acute erythroleukemic leukemia, acute lymphoblasticB-cell leukemia, acute lymphoblastic T-cell leukemia, acutelymphoblastic leukemia, acute megakaryoblastic leukemia, acutemonoblastic leukemia, acute myeloblastic leukemia, acute myelomonocyticleukemia, acute nonlymphocytic leukemia, acute promyelocytic leukemia,acute undifferentiated leukemia, chronic lymphocytic leukemia, chronicmyelocytic leukemia, hairy cell leukemia, multiple myeloma, heavy chaindisease, Hodgkin's disease, multiple myeloma, non-Hodgkin's lymphoma,polycythemia vera, or Waldenstrom macroglobulinemia.

Compounds and pharmaceutical compositions provided by the presentdisclosure can be used to treat, for example, one or more of thefollowing cancers: acute lymphoblastic leukemia, acute myeloid leukemia,adrenocortical carcinoma, appendix cancer, astrocytoma, atypicalteratoid/rhabdoid tumor, basal cell carcinoma (nonmelanoma), B-celllymphoma, bladder cancer, bone cancer, brain and spinal cord tumors,brain stem cancer, brain tumor, breast cancer, bronchial tumors, Burkittlymphoma, carcinoid tumor, carcinoma of head and neck, central nervoussystem embryonal tumors, cerebellar astrocytoma, cerebralastrocytoma/malignant glioma, cervical cancer, chordoma, chroniclymphocytic leukemia, chronic myelogenous leukemia, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, desmoplastic small roundcell tumor, ductal carcinoma, dye cancer, endocrine pancreas tumors(islet cell tumors), endometrial cancer, ependymoblastoma, esophagealcancer, esthesioneuroblastoma, Ewing family of tumors, extracranial germcell tumor, extrahepatic bile duct cancer, gallbladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumor, gestational trophoblastic tumor, glioblastoma, glioma, hairy cellleukemia, head and neck cancer, heart cancer, hematopoetic tumors of thelymphoid lineage, hepatocellular cancer, Hodgkin lymphoma,hypopharyngeal cancer, hypothalamic and visual pathway glioma,IDs-related lymphoma, intraocular melanoma, islet cell tumors, Kaposisarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer,leukemia, lip and oral cavity cancer, male breast cancer, malignantfibrous histiocytoma, malignant germ cell tumors, malignantmesothelioma, medulloblastoma, melanoma, Merkel cell carcinoma,mesothelioma, mouth cancer, multiple endocrine neoplasia syndrome,multiple myeloma, mycosis fungoides, myelodysplastic, myeloproliferativeneoplasms, nasal cavity and paranasal sinus cancer, nasopharyngealcancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer,oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarianepithelial cancer, ovarian germ cell tumor, ovarian low malignantpotential tumor, pancreatic cancer, pancreatic neuroendocrine tumors(islet cell tumors), papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pheochromocytoma, pineal parenchymal tumors, pineoblastoma andsupratentorial primitive neuroectodermal tumors, pituitary tumor, plasmacell neoplasm/multiple myeloma, pleuropulmonary blastoma, pregnancy andbreast cancer, primary central nervous system lymphoma, primary livercancer, primary metastatic squamous neck cancer with occult, prostatecancer, rectal cancer, renal cell cancer, renal pelvis and ureter,respiratory tract carcinoma, retinoblastoma, rhabdomyosarcoma, salivarygland cancer, sarcoma, Sézary syndrome, skin cancer, small intestinecancer, soft tissue sarcoma, squamous cell carcinoma (nonmelanoma),stomach cancer, supratentorial primitive neuroectodermal tumors, T-celllymphoma, testicular cancer, throat cancer, thymoma and thymiccarcinoma, thyroid cancer, transitional cell cancer, urethral cancer,uterine sarcoma, vaginal cancer, visual pathway and hypothalamic glioma,vulvar cancer, Waldenström macroglobulinemia, Wilms tumor, and systemicand central metastases of any of the foregoing.

Methods provided by the present disclosure include methods of treatingcancer, where the cancer is selected from breast cancer and melanoma.

Methods provided by the present disclosure include methods of treatingan inflammatory disease in a patient comprising administering to apatient in need thereof a therapeutically effective amount of a compoundor pharmaceutical composition provided by the present disclosure.

Examples of inflammatory diseases include allergy, Alzheimer's disease,anemia, ankylosing spondylitis, arthritis, atherosclerosis, asthma,autism, arthritis, carpal tunnel syndrome, celiac disease, colitis,Crohn's disease, congestive heart failure, dermatitis, diabetes,diverticulitis, eczema, fibromyalgia, fibrosis, gall bladder diseasegastroesophageal reflux disease, Hashimoto's thyroiditis, heart attack,hepatitis, irritable bowel syndrome, kidney failure, lupus, multiplesclerosis, nephritis, neuropathy, pancreatitis, Parkinson's disease,psoriasis, polymyalgia rheumatica, rheumatoid arthritis, scleroderma,stroke, surgical complications, and ulcerative colitis.

Methods provided by the present disclosure include methods of treatingan inflammatory disease in a patient, where the inflammatory disease isselected from, for example, acute respiratory distress syndrome, focalsegmental glomerulonephritis, atherosclerosis/acute coronary syndrome,chronic obstructive pulmonary disease, asthma, inflammatory boweldisease, Crohn's disease, psoriasis, lupus, multiple sclerosis,inflammation in hypercholesteremia, pain, diabetes including Type 1diabetes and Type 2 diabetes, and rheumatoid arthritis.

Methods provided by the present disclosure include methods of treatingan autoimmune disease in a patient comprising administering to a patientin need thereof a therapeutically effective amount of a compound orpharmaceutical composition provided by the present disclosure.

A compound or a pharmaceutical composition provided by the presentdisclosure can be useful in treating autoimmune diseases. Autoimmunediseases can be defined as human diseases in which the immune systemattacks its own proteins, cells, and/or tissues. A comprehensive listingand review of autoimmune diseases can be found, for example, in TheAutoimmune Diseases, Rose and Mackay, 2014, Academic Press.

Examples of autoimmune diseases include Addison's disease,agammaglobulinemia, alopecia areata, amyloidosis, ankylosingspondylitis, anti-GBM/anti-TBN nephritis, antiphospholipid syndrome,autoimmune angioedema, autoimmune dysautonomia, autoimmuneencephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease,autoimmune myocarditis, autoimmune pancreatitis, autoimmune retinopathy,autoimmune urticaria, axonal and neuronal neuropathy, Balo disease,Bechet's disease, benign mucosal pemphigoid, bullous pemphigoid,Castleman disease, celiac disease, Chagas disease, chronic inflammatorydemyelinating polyneuropathy, chronic recurrent multifocalosteomyelitis, Churg-Strauss, cicatricial pemphigoid, Cogan' syndrome,cold agglutinin disease, congenital heart block, Coxcackie myocarditis,CREST syndrome, Crohn's disease, dermatitis herpetiformis,dermatomyositis, Devic's disease, discoid lupus, Dressler's syndrome,endometriosis, eosinophilic esophagitis, eosinophilic fasciitis,erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome,fibromyalgia, fibrosing alveolitis, giant cell arteritis, giant cellmyocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosiswith polyangiitis, Graves' disease, Gullain-Barre syndrome, Hashimoto'sthyroiditis, hemolytic anemia, Henoch-Schoenlein purpura, herpesgestationis or pemphigoid gestationis, hypogammaglobulinemia, IgAnephropathy, IgG4-related sclerosing disease, immune thrombocytopenicpurpura, inclusion body myositis, interstitial cystitis, juvenilearthritis, juvenile diabetes, juvenile myositis, Kawasaki disease,Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus,lichen sclerosis, ligneous conjunctivitis, linear IgA disease, lupus,Lyme disease chronic, Meniere's diseases, microscopic polyangiitis,mixed connective tissue disease, Mooren's ulcer, Mucha Habermanndisease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy,neuromyelitis, optica, neutropenia, ocular cicatricial pemphigoid, opticneuritis, palindromic rheumatism, PANDAS, paraneoplastic cerebellardegeneration, paroxysmal nocturnal hemoglobinuria, Parry Rombergsyndrome, pars planitis, Parsonnage-Turner syndrome, pemphigus,peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia,POEMS syndrome, polyarteritis nodosa, polyglandular syndromes,polymyalgia rheumatica, polymyositis, postmyocardial infarctionsyndrome, postpericardiotomy syndrome, primary biliary cirrhosis,primary sclerosing cholangitis, progesterone dermatitis, psoriasis,psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum,Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy,relapsing polychondritis, restless legs syndrome, retroperitonealfibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidtsyndrome, scleritis, scleroderma, Sjogren's syndrome, sperm andtesticular autoimmunity, stiff person syndrome, subacute bacterialendocarditis, Susac's syndrome, sympathetic ophthalmia, Takayasu'sarteritis, temporal arteritis, thrombocytopenic purpura, Tolosa-Huntsyndrome, transverse myelitis, type 1 diabetes, ulcerative colitis,undifferentiated connective tissue disease, uveitis, vaculitis,vitiligo, and Wegener's granulomatosis.

A compound or a pharmaceutical composition provided by the presentdisclosure can be used to treat autoimmune disorders such as, forexample, lupus, graft-versus-host disease, hepatitis C-inducedvasculitis, Type I diabetes, multiple sclerosis, spontaneous loss ofpregnancy, an atopic disease, and an inflammatory bowel disease.

A compound or a pharmaceutical composition provided by the presentdisclosure can be administered with one or more additional therapeuticagents for treating an autoimmune disease. A compound of Formula (6) ora pharmaceutical composition thereof may be administered in conjunctionwith one or more immunosuppressants including, for example,corticosteroids such as prednisone, budesonide, and prednisolone; Januskinase inhibitors such as tofacitinib; calcineurin inhibitors such ascyclosporine and tacrolimus; mTOR inhibitors such as sirolimus andeverolimus; IMDH inhibitors such as azathioprine, leflunomide, andmycophenolate; biologics such as abatacept adalimumab, anakinra,certolizumab, etanercept, golimumab, infliximab, ixekizumab,natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, andvedolizumab; and monoclonal antibodies such as basiliximab anddaclizumab.

Methods provided by the present disclosure include methods of treating adisease in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a compound orpharmaceutical composition provided by the present disclosure, whereinthe disease is selected from acute coronary syndrome, acute lung injury,acute respiratory distress syndrome (ARDS), Alzheimer's disease, asthma,a cardiovascular disease, chronic obstructive pulmonary disease (COPD),inflammatory bowel disease, major depressive disorder, multiplesclerosis, neuropathic pain, and rheumatoid arthritis.

A compound or a pharmaceutical composition provided by the presentdisclosure can be administered with one or more additional therapeuticagents for treating an age-related disease such as hearing loss, muscleregeneration, and Werner's syndrome.

Methods provided by the present disclosure include methods of treating adisease in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a compound orpharmaceutical composition provided by the present disclosure, whereinthe disease is an age-related disease such as, for example, hearingloss, muscle degeneration, Werner's syndrome, cellular aging, orAlzheimer's disease.

Methods provided by the present disclosure include methods of treating adisease in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a compound orpharmaceutical composition provided by the present disclosure, whereinthe disease is selected from sudden idiopathic hearing loss, druginduced hearing loss, age-related hearing loss, and Duchenne musculardystrophy.

Methods provided by the present disclosure include methods of treating aviral disease in a patient comprising administering to a patient in needthereof a therapeutically effective amount of a compound orpharmaceutical composition provided by the present disclosure. A viraldisease can be SARS-CoV-19 and SARS-CoV-2.

The amount of a compound of Formula (6) provided by the presentdisclosure, or pharmaceutical composition thereof that will be effectivein the treatment of a disease can depend, at least in part, on thenature of the disease, and may be determined by standard clinicaltechniques known in the art. In addition, in vitro or in vivo assays maybe employed to help identify optimal dosing ranges. Dosing regimens anddosing intervals may also be determined by methods known to thoseskilled in the art. The amount of a compound of Formula (6) provided bythe present disclosure administered may depend on, among other factors,the patient being treated, the weight of the patient, the severity ofthe disease, the route of administration, and the judgment of theprescribing physician.

For systemic administration, a therapeutically effective dose may beestimated initially from in vitro assays. Initial doses may also beestimated from in vivo data, e.g., animal models, using techniques thatare known in the art. Such information may be used to more accuratelydetermine useful doses in humans. One having ordinary skill in the artmay optimize administration to humans based on animal data.

A dose of a compound of Formula (6) provided by the present disclosureand appropriate dosing intervals may be selected to maintain a sustainedtherapeutically effective concentration of a compound of Formula (6)provided by the present disclosure in the blood of a patient, and incertain embodiments, without exceeding a minimum adverse concentration.

A pharmaceutical composition comprising a compound of Formula (6)provided by the present disclosure may be administered, for example onceper week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, orevery 6 weeks. Dosing may be provided alone or in combination with otherdrugs and may continue as long as required for effective treatment ofthe disease. Dosing may also be undertaken using continuous orsemi-continuous administration over a period of time. Dosing includesadministering a pharmaceutical composition to a mammal, such as a human,in a fed or fasted state.

A pharmaceutical composition may be administered in a single dosage formor in multiple dosage forms or as a continuous or an accumulated doseover a period of time. When multiple dosage forms are used the amount ofa compound of Formula (6) provided by the present disclosure containedwithin each of the multiple dosage forms may be the same or different.

Suitable daily dosage ranges for administration can range, for example,from about 2 μg to about 200 mg of a compound of Formula (6) provided bythe present disclosure per kilogram body weight.

Suitable daily dosage ranges for administration may range, for example,from about 1 μg to about 50 mg of a compound of Formula (6) provided bythe present disclosure per square meter (m²) of body surface.

A compound of Formula (6) provided by the present disclosure may beadministered to treat cancer in a patient in an amount, for example,from 0.001 mg/day to 100 mg/day, or in any other appropriate daily dose.A dose can be, for example, from 0.01 μg/kg body weight/week to 100μg/kg body weight/week or any other suitable dose.

A pharmaceutical composition comprising a compound of Formula (6)provided by the present disclosure may be administered to treat cancerin a patient so as to provide a therapeutically effective concentrationof a compound of Formula (6) provided by the present disclosure in theblood or plasma of the patient. A therapeutically effectiveconcentration of a compound of a compound of Formula (6) provided by thepresent disclosure in the blood of a patient can be, for example, from0.01 μg/L to 1,000 μg/L, from 0.1 μg/L to 500 μg/L, from 1 μg/L to 250μg/L, or from about 10 μg/L to about 100 μg/L. A therapeuticallyeffective concentration of a compound of Formula (6) provided by thepresent disclosure in the blood of a patient can be, for example, atleast 0.01 μg/L, at least 0.1 μg/L, at least 1 μg/L, at least about 10μg/L, or at least 100 μg/L. A therapeutically effective concentration ofa compound of Formula (6) in the blood of a patient can be, for example,less than an amount that causes unacceptable adverse effects includingadverse effects to homeostasis. A therapeutically effectiveconcentration of a compound of Formula (6) in the blood of a patient canbe an amount sufficient to restore and/or maintain homeostasis in thepatient.

Pharmaceutical compositions provided by the present disclosure may beadministered to treat a disease in a patient so as to provide atherapeutically effective concentration of a compound of Formula (6) inthe blood of a patient for a period of time such as, for example, for 4hours, 8 hours, 12 hours, 16 hours, 20 hours, 1 day, or 2 days.

The amount of a compound of Formula (6) administered may vary during atreatment regimen.

Pharmaceutical compositions provided by the present disclosure mayfurther comprise one or more pharmaceutically active compounds inaddition to a compound of Formula (6). Such compounds may be provided,for example, to treat the cancer being treated with the compound ofFormula (6) or to treat a disease, disorder, or condition other than thecancer being treated with the compound of Formula (6), to treat aside-effect caused by administering the compound of Formula (6), toaugment the efficacy of the compound of Formula (6), and/or to modulatethe activity of the compound of Formula (6).

A compound of Formula (6) provided by the present disclosure may beadministered in combination with at least one other therapeutic agent. Acompound of Formula (6) may be administered to a patient together withanother compound for treating cancer in the patient. The at least oneother therapeutic agent can be a second, different compound of Formula(6). A compound of Formula (6) and the at least one other therapeuticagent may act additively or, and in certain embodiments, synergisticallywith another compound of Formula (6). The at least one additionaltherapeutic agent may be included in the same pharmaceutical compositionor vehicle comprising the compound of Formula (6) or may be in aseparate pharmaceutical composition or vehicle. Accordingly, methodsprovided by the present disclosure further include, in addition toadministering a compound of Formula (6), administering one or moretherapeutic agents effective for treating cancer or a different disease,disorder or condition than cancer. Methods provided by the presentdisclosure include administration of a compound of Formula (6) and oneor more other therapeutic agents provided that the combinedadministration does not inhibit the therapeutic efficacy of the compoundof Formula (6) and/or does not produce adverse combination effects.

A pharmaceutical composition comprising a compound of Formula (6) may beadministered concurrently with the administration of another therapeuticagent, which may be part of the same pharmaceutical composition as, orin a different pharmaceutical composition than that comprising acompound of Formula (6). A compound of Formula (6) may be administeredprior or subsequent to administration of another therapeutic agent. Incertain combination therapies, the combination therapy may comprisealternating between administering a compound of Formula (6) and acomposition comprising another therapeutic agent, e.g., to minimizeadverse drug effects associated with a particular drug. When a compoundof Formula (6) is administered concurrently with another therapeuticagent that potentially may produce an adverse drug effect including, forexample, toxicity, the other therapeutic agent may be administered at adose that falls below the threshold at which the adverse drug reactionis elicited.

A pharmaceutical composition comprising a compound of Formula (6)provided by the present disclosure may be administered with one or moresubstances, for example, to enhance, modulate and/or control release,bioavailability, therapeutic efficacy, therapeutic potency, and/orstability, of the compound of Formula (6). For example, a pharmaceuticalcomposition comprising a compound of Formula (6) can be co-administeredwith an active agent having pharmacological effects that enhance thetherapeutic efficacy of the compound of Formula (6).

A compound of Formula (6), or a pharmaceutical composition thereof maybe administered in conjunction with an agent known or believed to beeffective in treating a disease such as cancer, an autoimmune disease oran inflammatory disease in a patient, such as the same disease beingtreated with the compound of Formula (6).

A compound of Formula (6), or a pharmaceutical composition thereof maybe administered in conjunction with an agent known or believed tointerfere with cell proliferation.

A compound of Formula (6), or a pharmaceutical composition thereof maybe administered in conjunction with an agent known or believed tointerfere with cellular metabolism, to be an anti-metabolite, tointerfere with RNA transcription, to interfere with RNA translation, tointerfere with cellular protein synthesis, to interfere with synthesisof precursors for DNA synthesis and replication, to interfere withpurine synthesis, to interfere with nucleoside synthesis, to interactwith mTOR, to be an mTOR inhibitor, to interfere with cell cyclecheckpoints.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with a checkpoint inhibitor including aCTLA-4 inhibitor such as ipilimumab, a PD-1 inhibitor such aspembrolizumab and nivolumab, and/or a PD-LI inhibitor such asatezolizumab, avelumab, and durvalumab. A compound of Formula (6) or apharmaceutical composition thereof may be administered in conjunctionwith an immunomodulator such as CD137/4-1BB, CD27, GIYR, and/or OC40.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with an agent known or believed to becytotoxic, to cause DNA damage, to cause cell cycle arrest, or to causemitotic catastrophe.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with an agent known or believed to modulateglutathione concentration, to modulate glutathione concentration withincells, to decrease glutathione concentration within cells, to reduceglutathione uptake into cells, to reduce glutathione synthesis, or toreduce glutathione synthesis within cells.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with an agent known or believed to interferewith neovascularization, to reduce neovascularization, or to promoteneovascularization.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with an agent known or believed to interferewith hormone homeostasis, to interfere with hormone synthesis, tointerfere with hormone receptor binding, or to interfere with hormonesignal transduction.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with an agent known or believed to interferewith growth factor homeostasis, to interfere with growth factor receptorexpression, to interfere with growth factor binding to growth factorreceptors, to interfere with growth factor receptor signal transduction,to interfere with the Hedgehog (Hh) signaling, to inhibit the Hedgehogpathway signaling, to inhibit ALK (anaplastic lymphoma kinase) pathwaysignaling, or to inhibit the non-homologous end joining (NHEJ) pathway.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with one or more agents known or believed tobe a VEGFR (vascular endothelial growth factor receptor) inhibitor, aRTK (receptor tyrosine kinase) inhibitor, a sodium channel currentblocker, aFAK (focal adhesion kinase) inhibitor, a GLI(glioma-associated oncogene) inhibitor, a GLI1 inhibitor, a GLI2inhibitor, a GLI3 inhibitor, a MAPK (mitogen-activated protein kinase)inhibitor, a MAPK/ERK pathway (also known as Ras-Raf-MEK-ERK pathways)inhibitor, a MEK1 inhibitor, a MEK2 inhibitor, a MEK5 inhibitor, aMEK5/ERK5 inhibitor, aRTA (renal tubular acidosis) inhibitor, a ALK(anaplastic lymphoma kinase) inhibitor, Aa LK kinase inhibitor, anuclear translocation inhibitor, a PORCN (porcupine) inhibitor, a 5-ARI(5α-reductase inhibitor), topoisomerase inhibitor, a Ras (rat sarcoma)inhibitor, a K-ras inhibitor, a CERK (ceramide kinase) inhibitor, a PKB(protein kinase B, also known as AKT) inhibitor, a AKT1 inhibitor, EZH2(enhancer of zeste homolog 2) inhibitor, a BET (bromodomain andextraterminal domain motif) inhibitor, a SYK (spleen tyrosine kinase)inhibitor, JAK (Janus kinase) inhibitors, a SYK/JAK inhibitor, a IDO(indoleamine-pyrrole 2,3-dioxygenase) inhibitor, a IDO1 inhibitor, a RXR(retinoic X receptors) activating agent, a selective RXR activatingagent, a p-glycoprotein inhibitor, a ERK inhibitor, a PI3K(phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitor, a BRD(bromodomain-containing protein) inhibitor, a BRD2 inhibitor, a BRD3inhibitor, a BRD4 inhibitor, a BRDT (bromodomain testis-specificprotein) inhibitor, a reverse transcriptase inhibitor, a NRT (nucleosideanalog reverse-transcriptase) inhibitor, a PIM (proviral integrations ofMoloney virus) inhibitor, a EGFR (epidermal growth factor receptor)inhibitor, a photosensitizer, a radiosensitizer, a ROS (proto-oncogene,receptor tyrosine kinase) inhibitor, a ROS1 (proto-oncogene 1)inhibitor, a CK (casein kinase) inhibitor, a CK2 inhibitor, a Bcr-Abl(breakpoint cluster region-Abelson proto-oncogene) tyrosine-kinaseinhibitor such as dasatinib, a microtubule stabilizing agent, amicrotubule depolymerization/disassembly inhibitor, a DNA intercalator,an androgen receptor antagonist, a chemoprotective agents, a HDAC(histone deacetylase) inhibitor, a DPP (dipeptidyl peptidase) inhibitor,a DPP-4 inhibitor, BTK (Bruton's tyrosine kinase) inhibitor, a kinaseinhibitor such as imatinib, a tyrosine kinase inhibitor such asnilotinib, a ARP (poly (ADP-ribose) polymerase) inhibitor, a CDK(cyclin-dependent kinase) inhibitor, a CDK4 inhibitor, a CDK6 inhibitor,a CDK4/6 inhibitor, a HIF1α (hypoxia-inducible factor 1-α) inhibitor, aDNA ligase inhibitor, a DNA ligase IV inhibitor, a NHEJ (non-homologousend joining) inhibitor, a DNA ligase IV, a NHEJ inhibitor and a RAFinhibitor, a TKI and a RAF inhibitor, a TKI and RAF inhibitor such assorafenib, a PDT (photodynamic therapy) sensitizer, an ATR (ataxiatelangiectasia- and Rad3-related protein kinase) inhibitor, or acombination of any of the foregoing.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with one or more chemotherapeutic agents,such as, for example, a VEGFR inhibitor such as fruquintinib,motesanib/AMG-706, vatalanib; a RTK inhibitor such as ponatinib; asodium channel blocker such as GS967; a FAK inhibitor such as TAE226; aGLI1 and GLI2 inhibitor such as GANT61, a MEK inhibitor such asbinimetinib; a RTA inhibitor such as linifanib; an ALK inhibitor such asbrigstinib; bromopyruvic acid; a DNA alkylating agent such as thiotepa;nuclear translocations factors such as JSH-23; a PORCn inhibitor such asWnt-059; a 5α-reductase inhibitor such as dutasteride; a topoisomeraseinhibitor such as carubicin; a RAS inhibitor such as Kobe0065; a CerKinhibitor such as NVP-231; an AKT inhibitor such as uprosertib; a EZH2inhibitor such as GSK-503; a BET bromodomain inhibitor such as OTX015; aMEKS/ERKS inhibitor such as BIX02189; a Syl/JAK inhibitor such ascerdulatinib; an IDO1 inhibitor such as NLG919; a retinoic X receptoractivating agent such as bexsrotene; a PGP inhibitor such as acotiamideor actotiamide HCl; an Erk inhibitor such SCH772984; a PI3K inhibitorsuch as gedatolisib; a JAK inhibitor such as ruxolitinib; an AKTinhibitor such as afuresertib or afuresertib HCl; an ALK1 inhibitor suchas ceritinib; an HDAC inhibitor such as abexinostat; a DPP inhibitorsuch as oamarigliptin; an EGFR inhibitor such as gefittinib; an EZH2inhibitor such as GSK126; a BTK inhibitor such as ibrutinib; a kinaseinhibitor such as imatinin HCl; an IDO inhibitor such as INCB024360; aDNA crosslinker such as mitomycin C; a tyrosine kinase inhibitor such asnilotinib, a PARP inhibitor such as olaparib; a tubulin stabilizationpromoter such as paclitaxel; a CDK4/6 inhibitor such as palbociclib; aRTK inhibitor such as sunitinib; a PDT sensitizer such as tslsporfin; ap-glycoprotein inhibitor such as tariquidar; an ATR inhibitor such asVE-822; an HDAC inhibitor such as PCI-24781; a DPP inhibitor such asomarigliptin; an EGFR inhibitor such as gefinib; an EZH2 inhibitor suchas GSK126; a BTK inhibitor such as irbrutinib; an IDO inhibitor such asINCB024360; or a combination of any of the foregoing.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with another chemotherapeutic agent, suchas, for example, N-acetyl cysteine (NAC), adriamycin, alemtuzumab,amifostine, arsenic trioxide, ascorbic acid, bendamustine, bevacizumab,bortezomib, busulfan, buthionine sulfoxime, carfilzomib, carmustine,clofarabine, cyclophosphamide, cyclosporine, cytarabine, dasatinib,datinomycin, defibrotide, dexamethasone, docetaxel, doxorubicin,etoposide, filgrastim, floxuridine, fludarabine, gemcitabine, interferonalpha, ipilimumab, lenalidomide, leucovorin, melphalan, mycofenolatemofetil, paclitaxel, palifermin, panobinostat, pegfilrastim,prednisolone, prednisone, revlimid, rituximab, sirolimus, sodium2-mercaptoethane sulfonate (MESNA), sodium thiosulfate, tacrolimus,temozolomide, thalidomide, thioguanine, thiotepa, topotecan, velcade, ora combination of any of the foregoing.

A compound of Formula (6) or a pharmaceutical compositions thereof canbe used in combination therapy with other chemotherapeutic agentsincluding one or more antimetabolites such as folic acid analogs;pyrimidine analogs such as fluorouracil, floxuridine, and cytosinearabinoside; purine analogs such as mercaptopurine, thiogunaine, andpentostatin; natural products such as vinblastine, vincristine,etoposide, tertiposide, dactinomycin, daunorubicin, doxorubicin,bleomycin, mithamycin, mitomycin C, L-asparaginase, and interferonalpha; platinum coordination complexes such as cis-platinum, andcarboplatin; mitoxantrone; hydroxyurea; procarbazine; hormones andantagonists such as prednisone, hydroxyprogesterone caproate,medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol,ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone,flutamide, and leuprolide, anti-angiogenesis agents or inhibitors suchas angiostatin, retinoic acids, paclitaxel, estradiol derivatives, andthiazolopyrimidine derivatives; apoptosis prevention agents; triptolide;colchicine; luliconazole; and radiation therapy.

A compound of Formula (6) or a pharmaceutical composition thereof may beco-administered with a compound that inhibits DNA repair such as, forexample, O6-benzylguanine (O6-BG).

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with one or more chemotherapeutic agents,such as, for example, abarelix, abiraterone, abiraterone acetate,n-acetyl cysteine, aclarubicin hydrochloride, adriamycin, adenine,afatinib, afatinib dimaleate, alemtuzumab, alendronate sodium,alitretinoin, allopurinol sodium, altretamine, amifostine,aminoglutethimide, aminolevulinic acid, amrubicin, amsacrine,anastrozole, angiostatin, apremilast, aprepitant, arsenic trioxide,ascorbic acid, 1-asparaginase, azacitidine, azathioprine sodium,bazedoxifene (serm), belinostat, bendamustine hcl, O6-benzylguanine,bevacizumab, bexarotene, bicalutamide, biricodar, bleomycin sulfate,bortezomib, bosutinib, brivudine, buserelin, busulfan, buthioninesulfoxime, cabazitaxel, cabozantinib, capecitabine, carboplatin,carboquone, carfilzomib, carmofur, carmustine, ceritinib, chlorambucil,cisplatin, cladribine, clodronate disodium, clofarabine, crizotinib,cyclophosphamide, cyclosporine, cytarabine, cytosine arabinoside,dabrafenib, dacarbazine, dactinomycin, dasatinib, datinomycin,daunorubicin, decitabine, defribrotide, degarelix acetate,dexamethasone, dexrazoxane hydrochloride, diaziquone, diethylstilbestrol, docetaxel, doxifluridine, doxorubicin hydrochloride,doxorubicin free base, dromostanolone propionate, dutasteride,eltrombopag, enzalutamide, epirubicin hydrochloride, eribulin mesylate,erlotinib hydrochloride, estramustine phosphate sodium, ethinylestradiol, etoposide phosphate, etoposide, everolimus, exemestane,fentanyl, filgrastim, fingolimod, floxuridine, fludarabine phosphate,fluorouracil, fluoxymesterone, flutamide, formestane, formylmelphalan,fosaprepitant, fotemustine, fulvestrant, gefitinib, gemcitabinehydrochloride, gemcitabine free base, glutathione, glyciphosphoramide,glyfosfin, goserelin acetate, granisetron hydrochloride, heptaplatin,hexyl 5-aminolevulinate, histrelin acetate, hydroxyprogesteronecaproate, hydroxyurea, ibandronate sodium, ibrutinib, icotinib,idarubicin HCl, idelalisib, idoxuridine, ifosfamide, interferon alpha,imatinib mesylate, imiquimod, ingenol mebutate, ipilimumab, irinotecanhydrochloride, ixabepilone, lanreotide acetate, lapatinib free base,lapatinib ditosylate, lasofoxifene, lenalidomide, letrozole, leucovorincalcium, leuprolide acetate, levamisole hydrochloride, levoleucovorincalcium, iobenguane, lobaplatin, lomustine, maropitant, masoprocol,mechlorethamine hydrochloride, megestrol acetate, medroxyprogesteroneacetate, melphalan hydrochloride, mercaptopurine, mercaptoethanesulfonate sodium, methotrexate, methoxsalen, methyl aminolevulinate,methylene blue, methylisoindigotin, mifamurtide, miltefosine,miriplatin, mithamycin, mitobronitol, mitomycin C, mitotane,mitoxantrone hydrochloride, mycophenolate mofetil, nabiximols,nafarelin, nandrolone, nedaplatin, nelarabine, netupitant, nilotinib,nilutamide, nimustine, nintedanib, nocodazole, octreotide, olaparib,omacetaxine mepesuccinate, ondansetron hydrochloride, oxaliplatin,paclitaxel, palbociclib, palifermin, palonosetron hydrochloride,pamidronate disodium, panobinostat, pasireotide, pazopanibhydrochloride, pegfilrastim, pemetrexed disodium, pentostatin,peplomycin, pipobroman, pirarubicin, plerixafor, plicamycin,pomalidomide, ponatinib, porfimer sodium, porfiromycin, pralatrexate,prednimustine, prednisolone, prednisone, procarbazine hydrochloride,quinagolide hydrochloride, raloxifene, raltitrexed, radotinib,ranimustine, retinoic acids, revlimide, rituxinab, romidepsin,ruxolitinib, ruxolitinib phosphate, semustine, sirolimus, sodiumthiosulfate, sorafenib free base, sorafenib tosylate, streptozocin,sufentanil, sunitinib, tacrolimus, talaporfin sodium, tamibarotene,tamoxifen citrate, tapentadol, temoporfin, temozolomide, temsirolimus,teniposide, teriflunomide, tertiposide, testolactone, testosteronepropionate, thalidomide, thioguanine, thiotepa, thymalfasin, toceranibphosphate, topotecan hydrochloride, toremifene citrate, trabectedin,trametinib, tretinoin, trilostane, triptorelin, tropisetron, uramustine,valrubicin, vandetanib, vedotin, vemurafenib, verteporfin, vinblastine,vincristine sulfate, vincristine free base, vindesine, vinorelbinetartrate, vorinostat, and zoledronic acid.

A compound of Formula (6) or a pharmaceutical composition thereof may beadministered in conjunction with one or more chemotherapeutic agentssuch as, for example, abemaciclib, abiraterone acetate, ABVD, ABVE,ABVE-PC, AC, acalabrutinib, AC-T, ADE, ado-trastuzumab emtansine,afatinib dimaleate, aldesleukin, alectinib, alemtuzumab, alpelisib,amifostine, aminolevulinic acid hydrochloride, anastrozole, apalutamide,aprepitant, arsenic trioxide, asparaginase Erwinia chrysanthemi,atezolizumab, avelumab, axicabtagene ciloleucel, axitinib, azacitidine,BEACOPP, belinostat, bendamustine hydrochloride, BEP, bevacizumab,bexarotene, bicalutamide, binimetinib, bleomycin sulfate, blinatumomab,bortezomib, bosutinib, brentuximab vedotin, brigatinib, BuMel, busulfan,cabazitaxel, cabozantinib-s-malate, CAF, calaspargase pegol-mknl,capecitabine, caplacizumab-yhdp, CAPDX, carboplatin, carboplatin-taxol,carfilzomib, carmustine, carmustine implant, CEM, cemiplimab-rwlc,ceritinib, cetuximab, CEV, chlorambucil, chlorambucil-prednisone, CHOP,cisplatin, cladribine, clofarabine, CMF, cobimetinib, copanlisibhydrochloride, COPDAC, COPP, COPP-ABV, crizotinib, CVP,cyclophosphamide, cytarabine, cytarabine liposome, dabrafenib mesylate,dacarbazine, dacomitinib, dactinomycin, daratumumab, darbepoetin a,dasatinib, daunorubicin hydrochloride, daunorubicin hydrochloride andcytarabine liposome, decitabine, defibrotide sodium, degarelix,denileukin diftitox, denosumab, dexamethasone, dexrazoxanehydrochloride, dinutuximab, docetaxel, doxorubicin hydrochloride,doxorubicin hydrochloride liposome, durvalumab, duvelisib, elotuzumab,eltrombopag olamine, emapalumab-lzsg, enasidenib mesylate, encorafenib,enzalutamide, epirubicin hydrochloride, EPOCH, epoetin a, erdafitinib,eribulin mesylate, erlotinib hydrochloride, etoposide, etoposidephosphate, everolimus, exemestane, fec, filgrastim, fludarabinephosphate, fluorouracil injection, fluorouracil—topical, flutamide,folfiri, folfiri-bevacizumab, folfiri-cetuximab, folfirinox, folfox,fostamatinib disodium, FU-LV, fulvestrant, gefitinib, gemcitabinehydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin,gemtuzumab ozogamicin, gilteritinib fumarate, glasdegib maleate,glucarpidase, goserelin acetate, granisetron, HPV bivalent vaccine, HPVbivalent vaccine, recombinant HPV nonavalent vaccine, HPV nonavalentvaccine, recombinant, HPV quadrivalent vaccine, HPV uadrivalent vaccinerecombinant, hydroxyurea, hyper-CVAD, ibritumomab tiuxetan, ibrutinib,ICE, idarubicin hydrochloride, idelalisib, ifosfamide, imatinibmesylate, imiquimod, inotuzumab ozogamicin, interferon α-2b recombinant,iobenguane ¹³¹I, ipilimumab, irinotecan hydrochloride, irinotecanhydrochloride liposome, ivosidenib, ixabepilone, ixazomib citrate, JEB,lanreotide acetate, lapatinib ditosylate, larotrectinib sulfate,lenalidomide, lenvatinib mesylate, letrozole, leucovorin calcium,leuprolide acetate, lomustine, lorlatinib, lutetium Lu 177-dotatate,mechlorethamine hydrochloride, megestrol acetate, melphalan, melphalanhydrochloride, mercaptopurine, mesna, methotrexate, methylnaltrexonebromide, midostaurin, mitomycin c, mitoxantrone hydrochloride,mogamulizumab-kpkc, moxetumomab pasudotox-tdfk, MVAC, necitumumab,nelarabine, neratinib maleate, netupitant and palonosetronhydrochloride, nilotinib, nilutamide, niraparib tosylate monohydrate,nivolumab, obinutuzumab, OEPA, ofatumumab, OFF, olaparib, olaratumab,omacetaxine mepesuccinate, ondansetron hydrochloride, OPPA, osimertinibmesylate, oxaliplatin, paclitaxel, paclitaxel albumin-stabilizednanoparticle formulation, PAD, palbociclib, palifermin, palonosetronhydrochloride, palonosetron hydrochloride and netupitant, pamidronatedisodium, panitumumab, panobinostat, pazopanib hydrochloride, PCV, PEB,pegaspargase, pegfilgrastim, peginterferon α-2b, pembrolizumab,pemetrexed disodium, pertuzumab, plerixafor, polatuzumab vedotin-piiq,pomalidomide, ponatinib hydrochloride, pralatrexate, prednisone,procarbazine hydrochloride, propranolol hydrochloride, radium 223dichloride, raloxifene hydrochloride, ramucirumab, rasburicase,ravulizumab-cwvz, R-CHOP, R-CVP, recombinant HPV bivalent vaccine,recombinant HPV nonavalent vaccine, recombinant HPV quadrivalentvaccine, recombinant interferon α-2b, regorafenib, R-EPOCH, ribociclib,R-ICE, rituximab, rituximab and hyaluronidase human, rolapitanthydrochloride, romidepsin, romiplostim, rucaparib camsylate, ruxolitinibphosphate, siltuximab, sipuleucel-t, sonidegib, sorafenib tosylate,STANFORD V, sunitinib malate, TAC, tagraxofusp-erzs, talazoparibtosylate, talc, talimogene laherparepvec, tamoxifen citrate,temozolomide, temsirolimus, thalidomide, thioguanine, thiotepa,tisagenlecleucel, tocilizumab, topotecan hydrochloride, toremifene, TPF,trabectedin, trametinib, trastuzumab, trastuzumab andhyaluronidase-oysk, trifluridine and tipiracil hydrochloride, uridinetriacetate, VAC, Valrubicin, VAMP, vandetanib, VeIP, vemurafenib,venetoclax, vinblastine sulfate, vincristine sulfate liposome,vinorelbine tartrate, vip, vismodegib, vorinostat, XELIRI, XELOX,Ziv-aflibercept, zoledronic acid, and combinations of any of theforegoing.

A compound provided by the present disclosure or a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof can beadministered to a patient in conjunction with another compound known tobe useful tor treating the inflammatory disease, the autoimmunediseases, or the age-related disease being treated by the compoundprovided by the present disclosure.

The efficacy of administering a compound of Formula (6) or apharmaceutical composition thereof for treating cancer, an inflammatorydisease, or an autoimmune disease may be assessed using in vitro andanimal studies and in clinical trials.

Methods of inhibiting p38α MAPK provided by the present disclosureinclude contacting p38α MAPK with a compound provided by the presentdisclosure to a pocket near the ED substrate-docking site of p38α MAPK.

Methods of inhibiting p38α MAPK provided by the present disclosure donot result in loss of p38α-dependent counterregulatory responses. Thep38α-dependent counterregulatory response relates to mitogen- andstress-activated protein kinase-I (MSK1), or MSK2. In targeting a pocketnear the ED substrate-docking site of p38α, the inhibitors provided bythe present disclosure avoid interfering with CD-specific substrates,including MSK1/2, thus limiting inflammation through expression of IL-10and DUSP2.

ASPECTS OF THE INVENTION

Aspect 1. A compound having the structure of Formula (6):

or a pharmaceutically acceptable salt thereof, wherein,

-   -   R¹ is selected from C₁₋₄ alkanediyl, C₁₋₄ heteroalkanediyl,        substituted C₁₋₄ alkanediyl, and substituted C₁₋₄        heteroalkanediyl;    -   R² is substituted C₅₋₁₂ heterocycloalkyl;    -   R³ is selected from —C(═O)— and —S(═O)₂—; and    -   R⁴ is selected from —N(R⁵)₂ wherein each R⁵ is independently        selected from hydrogen and C₁₋₄ alkyl.

Aspect 2. The compound of aspect 1, wherein each of the one or moresubstituents is independently selected from —OH, ═O, —NH₂, —NO₂, C₁₋₆alkyl, C₁₋₆ cycloalkyl, C₆ aryl, C₁₋₆ heteroalkyl, C₁₋₆heterocycloalkyl, and C₅₋₆ heteroaryl.

Aspect 3. The compound of aspect 1, wherein each of the one or moresubstituents is independently selected from —OH, ═O, —NH₂, —NO₂, C₁₋₃alkyl, and C₁₋₃ heteroalkyl.

Aspect 4. The compound of aspect 1, wherein each of the one or moresubstituents is independently selected from —OH, ═O, and C₁₋₃ alkyl.

Aspect 5. The compound of aspect 1, wherein each of the one or moresubstituents is ═O.

Aspect 6. The compound of any one of aspects 1 to 5, wherein R¹ is C₁₋₄alkanediyl.

Aspect 7. The compound of any one of aspects 1 to 5, wherein R¹ isethanediyl.

Aspect 8. The compound of any one of aspects 1 to 5, wherein R¹ ismethanediyl.

Aspect 9. The compound of any one of aspects 1 to 5, wherein R² issubstituted C₆ heterocycloalkyl.

Aspect 10. The compound of aspect 9, wherein each of the one or moreheteroatoms is independently selected from O and N.

Aspect 11. The compound of any one of aspects 1 to 10, wherein R² ismorpholin-4-yl.

Aspect 12. The compound of any one of aspects 1 to 10, wherein R² ismono-substituted morpholin-4-yl.

Aspect 13. The compound of any one of aspects 1 to 10, wherein R² is3-substituted morpholin-4-yl.

Aspect 14. The compound of any one of aspects 12 to 13, wherein each ofthe one or more substituents is independently selected from —OH, ═O,—N(R⁵)₂, wherein each R⁵ is independently selected from hydrogen andC₁₋₃ alkyl.

Aspect 15. The compound of any one of aspects 12 to 13, wherein each ofthe one or more substituents is —OH,

Aspect 16. The compound of any one of aspects 12 to 13, wherein each ofthe one or more substituents is ═O.

Aspect 17. The compound of any one of aspects 12 to 13, wherein each ofthe one or more substituents is —N(R⁵)₂, wherein each R⁵ isindependently selected from hydrogen and C₁₋₃ alkyl.

Aspect 18. The compound of any one of aspects 1 to 17, wherein R³ isselected from —C(═O)— and —S(O)₂—.

Aspect 19. The compound of any one of aspects 1 to 17, wherein R³ is—C(═O)—.

Aspect 20. The compound of any one of aspects 1 to 17, wherein R³ is—S(O)₂—.

Aspect 21. The compound of any one of aspects 1 to 20, wherein R⁴ isbonded to the 3-position, the 4-position, the 5-position, the6-position, or the 7-position of the naphthyl moiety.

Aspect 22. The compound of any one of aspects 1 to 20, wherein R⁴ isbonded to the 5-position of the naphthyl moiety.

Aspect 23. The compound of aspect 1, wherein,

R¹ is C₁₋₃ alkanediyl;

R² is substituted 4-morpholinyl;

R³ is selected from —C(═O)— and —S(O)₂—; and

R⁴ is selected from —N(R⁵)₂ wherein each R⁵ is independently selectedfrom hydrogen and C₁₋₃ alkyl.

Aspect 24. The compound of aspect 1, wherein,

R¹ is methane-diyl;

R² is substituted 4-morpholinyl;

R³ is —S(O)₂—; and

R⁴ is —N(R⁵)₂ wherein each R⁵ is independently selected from hydrogenand methyl.

Aspect 25. The compound of any one of aspects 23 to 24, wherein R² is3-substituted 4-morpholinyl.

Aspect 26. The compound of any one of aspects 23 to 25, wherein in amoiety of R², the substituent is ═O.

Aspect 27. The compound of any one of aspects 23 to 26, wherein R⁴ isselected from —NH(—CH₃) and —N(—CH₃)₂.

Aspect 28. The compound of aspect 1, wherein the compound is selectedfrom:

4-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

4-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

4-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

6-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

6-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;and

6-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;

or a pharmaceutically acceptable salt of any of the foregoing.

Aspect 29. The compound of aspect 1, wherein the compound is5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(Compound 5) or a pharmaceutically acceptable salt thereof:

Aspect 30. The compound of aspect 1, wherein the compound is5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(2) or a pharmaceutically acceptable salt thereof:

Aspect 31. The compound of aspect 1, wherein the compound is5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(3) or a pharmaceutically acceptable salt thereof:

Aspect 32. The compound of any one of aspects 1 to 31, wherein thecompound inhibits the p38α MAPK receptor.

Aspect 33. The compound of any one of aspects 1 to 32, wherein thecompound selectively inhibits the p38α MAPK receptor.

Aspect 34. The compound of any one of aspects 1 to 33, wherein thecompound has a higher binding affinity to the p38α MAPK subunit than tothe p38β MAPK subunit.

Aspect 35. The compound of any one of aspects 1 to 34, wherein thecompound binds to a selective binding site of p38α MAPK, wherein thebinding pocket is defined by at least residues R49, H107, L108, and K165of p38α MAPK.

Aspect 36. The compound of aspect 35, wherein the compound competitivelybinds to the selective binding site competitively with4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide.

Aspect 37. The compound of any one of aspects 1 to 36, wherein thecompound inhibits MK2 phosphorylation induced by4-chloro-N-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)benzamide inanisomycin-stimulated HeLa cells.

Aspect 38. A pharmaceutical composition comprising the compound of anyone of aspects 1 to 37 or a pharmaceutically acceptable salt thereof.

Aspect 39. The pharmaceutical composition of aspect 38, wherein thepharmaceutical composition comprises a therapeutically effective amountof the compound of any one of aspects 1 to 37 or a pharmaceuticallyacceptable salt thereof for treating a disease in a patient.

Aspect 40. The pharmaceutical composition of aspect 39, wherein thedisease is treated by inhibiting the p38α MAPK receptor.

Aspect 41. The pharmaceutical composition of aspect 39, wherein thedisease is cancer.

Aspect 42. The pharmaceutical composition of aspect 39, wherein thedisease is an inflammatory disease.

Aspect 43. The pharmaceutical composition of aspect 39, wherein thedisease is an autoimmune disease.

Aspect 44. The pharmaceutical composition of aspect 39, wherein thedisease is selected from acute lung injury, acute respiratory distresssyndrome (ARDS), and chronic obstructive pulmonary disease (COPD).

Aspect 45. A method of treating a disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof, wherein the disease is treatedby inhibiting the p38α MAPK receptor.

Aspect 46. A method of treating a disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof, wherein the disease is cancer.

Aspect 47. The method of aspect 46, wherein the cancer is selected frombreast cancer and melanoma.

Aspect 48. A method of treating a disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof, wherein the disease is aninflammatory disease.

Aspect 49. The method of aspect 48, wherein the inflammatory disease isselected from acute respiratory distress syndrome, focal segmentalglomerulonephritis, atherosclerosis/acute coronary syndrome, chronicobstructive pulmonary disease, asthma, inflammatory bowel disease,Crohn's disease, psoriasis, lupus, multiple sclerosis, inflammation inhypercholesteremia, pain, diabetes, and rheumatoid arthritis.

Aspect 50. A method of treating a disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof, wherein the disease is anautoimmune disease.

Aspect 51. The method of aspect 50, wherein the autoimmune disease isselected from lupus, graft-versus-host disease, hepatitis C-inducedvasculitis, Type I diabetes, multiple sclerosis, spontaneous loss ofpregnancy, an atopic disease, and an inflammatory bowel disease.

Aspect 52. A method of treating a disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof, wherein the disease is anage-related disease.

Aspect 53. The method of aspect 52, wherein the age-related disease isselected from hearing loss, muscle degeneration, Werner's syndrome,cellular aging, and Alzheimer's disease.

Aspect 54. A method of treating a disease in a patient comprisingadministering to a patient in need of such treatment a therapeuticallyeffective amount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof, wherein the disease isselected from acute lung injury, acute respiratory distress syndrome(ARDS), and chronic obstructive pulmonary disease (COPD).

Aspect 55. A method of inhibiting the p38α MAPK receptor comprisingcontacting the p38α MAPK receptor with the compound of any one ofaspects 1 to 37 or a pharmaceutically acceptable salt thereof.

Aspect 56. A method of inhibiting the p38α MAPK receptor in a patientcomprising administering to a patient a pharmacologically effectiveamount of the compound of any one of aspects 1 to 37 or apharmaceutically acceptable salt thereof.

Aspect 57. The method of aspect 56, wherein inhibiting the p38α MAPKreceptor comprises selectively inhibiting the p38α MAPK receptor.

Aspect 58. The method of aspect 57, wherein inhibiting the p38α MAPKreceptor does not result in loss of a p38α-dependent counterregulatoryresponse.

Aspect 59. The method of aspect 58, wherein the p38α-dependentcounterregulatory response relates to mitogen- and stress-activatedprotein kinase-1 (MSK1) or MSK2.

Aspect 60. The method of any one of aspects 57 to 59, whereinselectively inhibiting the p38α MAPK receptor stabilizes an endothelialor epithelial barrier function.

Aspect 61. The method of any one of aspects 57 to 60, whereinselectively inhibiting the p38α MAPK receptor reduces inflammation.

Aspect 62. The method of any one of aspects 57 to 61, whereinselectively inhibiting the p38α MAPK receptor mitigates KPS-induced lunginjury.

Aspect 63. The method of any one of aspects 57 to 62, whereinselectively inhibiting the p38α MAPK receptor regulates leukocytetrafficking.

Aspect 64. The method of any one of aspects 57 to 63, whereinselectively inhibiting the p38α MAPK receptor regulates cytokineexpression.

EXAMPLES

The following examples describe in detail the synthesis of compounds ofFormula (6), the characterization of compounds of Formula (6) and usesof compounds of Formula (6). It will be apparent to those skilled in theart that many modifications, both to materials and methods, may bepracticed without departing from the scope of the disclosure.

Example 1 Synthesis of5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide(1)

Step 1: 5-(((Benzyloxy)carbonyl)amino)naphthalene-1-sulfonic acid (1b).

To a solution of 5-aminonaphthalene-1-sulfonic acid (1a) (50.2 g, 0.2249mol) in 0.1M NaHCO₃ (40 mL) was added 2M NaOH until the pH was adjustedto 10. Benzyl chloroformate (57.54 g, 0.3373 mol) was added to thestirred solution at 0° C. The temperature was raised to 25° C. andstirring was continued for 3 hours. LCMS showed a major peak as thetarget molecule. The reaction mixture was adjusted to pH 2 with 4M HCl,concentrated under reduced pressure, and purified by Biotage® IsoleraOne chromatography (C18 column, eluting with 10% to 95% MeCN/H₂Ocontaining 0.1% HCOOH) to afford5-(((benzyloxy)carbonyl)amino)naphthalene-1-sulfonic acid (1b) (30.5 g)as a purple solid. LCMS: m/z 355.9 [M+H]⁻.

Step 2: 5-5-(((Benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonicacid (1c).

To a solution of 5-(((benzyloxy)carbonyl)amino)naphthalene-1-sulfonicacid (1b) (30.5 g, 0.08534 mol) in dry DMF (300 mL) was added sodiumhydride (60% in mineral oil, 4.5 g, 0.1109 mol) at 0° C. Upon completionof the addition, the reaction mixture was stirred at 0° C. for 30minutes and iodomethane (15.7 g, 0.1109 mol) was added dropwise. Oncethe addition was complete, the resulting solution was stirred at 23° C.for 2 hours before being quenched with water. LCMS showed a major peakas the desired target molecule. The mixture was purified by Biotage®Isolera One chromatography (C18 column, eluting with 10% to 95% MeCN/H₂Ocontaining 0.1% HCOOH) to afford5(((benzyloxy)carbonyl)(methyl)amino)-naphthalene-1-sulfonic acid (1c)(12 g) as oil. LCMS: m/z 369.9 [M+H]⁻.

Step 3: Benzyl (5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate(1d).

A stirred mixture of5-(((benzyloxy)carbonyl)(methyl)amino)naphthalene-1-sulfonic acid (1c)(12 g, 0.03231 mol) and PCl₅ (6.73 g, 0.03231 mol) in toluene (100 mL)was heated at 120° C. for 3 hours. TLC indicated a new spot was formed.The reaction mixture was allowed to cool to 23° C. and concentratedunder vacuum and the result crude benzyl(5-(chlorosulfonyOnaphthalen-1-yl)(methyl)carbamate (1d), (16.17 g,about 80% purity on TLC) was used in the next step without furtherpurification. LCMS: m/z 427.1 [M+H]⁺.

Step 4: Benzylmethyl(5-(N-(4-(morpholinomethyl)phenyl)sulfamoyOnaphthalen-1-yl)carbamate(1e).

To a stirred solution of 4-(morpholinomethyl)aniline (3.66 g, 0.01731mol) in dichloromethane (60 mL) was added triethylamine (7.00 g, 0.06926mol) at 0° C. After stirring at the same temperature for 30 min, benzyl(5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate (1d) (6.75 g,0.01731 mol) was added. The resulting solution was stirred at overnightat 45° C., allowed to cool to room temperature, and quenched with water.LCMS showed the major peak as the desired target molecule. The mixturewas diluted with EtOAc, washed with water and saturated brine, driedwith anhydrous sodium sulfate, filtered and concentrated under vacuum.The resulting crude product was purified by column chromatograph onsilica gel (petroleum ether/ethyl acetate=10/1) to afford benzylmethyl(5-(N-(4-(morpholinomethyl)phenyl)sulfamoyl)naphthalen-1yl)-carbamate(1e), (4.6 g) as a yellow solid. LCMS: m/z 546.1 [M+H]⁺.

Step 5:5-(Methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide(1).

To a stirred solution of 8 (4.6 g, 0.00843 mol) in ethyl acetate (50 mL)was added 5% Pd/C (8 g). The reaction mixture was stirred at 23° C. for24 h under an atmosphere of H₂ (balloon). LCMS showed that the startingmaterial was consumed. The reaction mixture was filtered through Celite®plug and the resulting filtrate was concentrated under vacuum. Theresulting crude residue was purified by reverse phase Biotage® columnchromatography (40 g C18 column), ACN/water (0.1% HCOOH) 0-100%) to give5-(methylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamideof the title compound (1) (1.12 g) as a green-yellow solid. LCMS Rt=1.25min; m/z calculated for [M+H]+412.0. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57(s, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.26-8.16 (m, 1H), 7.94 (d, J=8.6 Hz,1H), 7.59-7.44 (m, 2H), 7.13 (s, 2H), 7.02 (s, 2H), 6.65 (d, J=4.9 Hz,1H), 6.59 (d, J=7.8 Hz, 1H), 3.57 (s, 4H), 2.88 (d, J=4.6 Hz, 3H), 2.28(s, 3H).

Example 2 Synthesis of5-(Methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(2)

Step 6: 4-(4-Nitrobenzyl)morpholin-3-one (2a).

A stirred mixture of morpholin-3-one (20 g, 0.1978 mol),1-(bromomethyl)-4-nitrobenzene (38.89 g, 0.1800 mol) and Cs₂CO₃ (116.65g, 0.3580 mol) in acetonitrile (300 mL) was heated at 80° C. for 2hours. The reaction mixture was allowed to cool to room temperature,filtered through a plug of Celite®, and the filtrate was concentratedunder vacuum. The resulting crude product was purified by columnchromatograph on silica gel (petroleum ether/ethyl acetate=1:1) toafford 4-(4-nitrobenzyl)morpholin-3-one (2a) (24.83 g) as a yellowsolid. LCMS: m/z 237.1 [M+H]⁺.

Step 7: 4-(4-Aminobenzyl)morpholin-3-one (2b).

To a stirred solution of 4-(4-nitrobenzyl)morpholin-3-one (2b) (24.8 g,0.1050 mol) in MeOH (5 mL) was added 10% Pd/C (6 g). The resultingmixture was stirred at room temperature for 1 hour under an atmosphereof H₂, (balloon). LCMS showed major peak was target molecule. Themixture was filtered through a bed of Celite® and the filtrate wasconcentrated under vacuum and the crude 4-(4-aminobenzyl)morpholin-3-one(2b) (18.4 g) was used in next step without any further purification.LCMS: m/z 207.1 [M+H]⁺. Step 8: Benzylmethyl(5-(N-(4-((3-oxomorpholino)methyl)phenyl)sulfamoyl)naphthalen-1-yl)carbamate(2c).

To a stirred solution of 4-(4-aminobenzyl)morpholin-3-one (2b) (4.53 g,0.02196 mol) in dichloromethane (70 mL) at 0° C. was added triethylamineTEA (8.89 g, 0.02416 mol), maintaining the temperature at 0° C. duringthe course of the addition. Upon completion of the addition, thereaction mixture was stirred at 0° C. for an additional 30 min. Benzyl(5-(chlorosulfonyl)naphthalen-1-yl)(methyl)carbamate (1d) (9.42 g,0.02416 mol) was added of the course of several minutes. The resultingsolution was stirred at 45° C., overnight. The reaction mixture wasallowed to cool to room temperature and quenched with H2O. LCMS showedmajor peak was target molecule. The mixture was diluted with EtOAc,washed with water and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The resulting crude product was purified bycolumn chromatograph on silica gel (petroleum ether/ethyl acetate=10/1)to afford benzylmethyl(5-(N-(4-((3-oxomorpholino)methyl)phenyl)-sulfamoyl)-naphthalen-1-yl)carbamate(2c) (5.3 g) as a yellow solid. LCMS: m/z 558.1 [M+H]⁻.

Step 9:5-(Methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(2).

To a stirred solution of benzylmethyl(5-(N-(4-((3-oxomorpholino)methyl)phenyl)-sulfamoyl)-naphthalen-1-yl)carbamate(2c) (5.3 g, 9.47 mmol) in ethyl acetate (50 mL) was added 10% Pd/C (10g). The mixture reaction was then stirred at 23° C. for 24 hours underH₂ (balloon). LCMS showed SM was consumed. The reaction was filteredthrough a plug of Celite and the resulting filtrate was concentratedunder vacuum. The resulting crude residue was purified by Biotage®reverse phase-column chromatography (40 g C18 column), acetonitrile/H₂O(0.1% HCOOH) 0-100%) to give5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)-naphthalene-1-sulfonamide(2) (1.02 g) as a green-yellow solid. LCMS (Shimadzu 2020): Rt=1.81 min;m/z calculated for [M+H]+426.15. ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s,1H), 8.36 (d, J=8.6 Hz, 1H), 8.13 (dd, J=7.4, 1.1 Hz, 1H), 7.87 (d,J=8.6 Hz, 1H), 7.50-7.39 (m, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.98-6.92 (m,2H), 6.58 (d, J=4.9 Hz, 1H), 6.52 (d, J=7.8 Hz, 1H), 4.32 (s, 2H), 4.01(s, 2H), 3.71 (t, J=5.9, 4.4 Hz, 2H), 3.09 (t, J=5.9, 4.4 Hz, 2H), 2.81(d, J=4.6 Hz, 3H).

Example 3 Synthesis of5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(3)

To a stirred solution of 4-(4-aminobenzyl)morpholin-3-one (2b) (7 g,0.03394 mol) in dichloromethane (70 mL) at 0° C. was added TEA (13.74 g,0.1358 mol), maintaining the reaction at 0° C. Upon completion ofaddition, the reaction mixture was stirred at 0° C. for 30 minutes.5-(Dimethylamino)naphthalene-1-sulfonyl chloride (1d) (10.07 g, 0.03733mol) was added over the course of a few minutes. The resulting solutionwas stirred overnight at 45° C. The reaction mixture was then allowed tocool to room temperature and quenched with water. LCMS showed the majorpeak as the desired target molecule. The mixture was diluted with EtOAc,washed with water and brine, dried over anhydrous Na₂SO₄, filtered andthe resulting filtrate was concentrated under vacuum. The resultingcrude product was purified by prep-HPLC (eluting with 30% to 100%H₂O/MeCN containing 0.1% HCOOH acid) and neutralized by 2M aqueous NaOHto afford5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)-naphthalene-1-sulfonamide(3) as a green solid. LCMS [M+H]+440.0. ¹H NMR (400 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.44 (d, J=8.5 Hz, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.21 (dd,J=7.4, 1.2 Hz, 1H), 7.60 (ddd, J=8.6, 7.5, 2.4 Hz, 2H), 7.25 (d, J=7.6Hz, 1H), 7.05 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.6 Hz, 2H), 4.36 (s, 2H),4.04 (s, 2H), 3.73 (dd, J=5.9, 4.4 Hz, 2H), 3.12 (t, J=5.2 Hz, 2H), 2.80(s, 6H).

Example 4 Synthesis of5-(dimethylamino)-N-(4-(morpholinomethyl)phenyl)naphthalene-1-sulfonamide(4)

The synthesis of compound (4) is disclosed in Example 9 of U.S.Application Publication No. 2020/0331874 A1.

Example 5 Bioanalysis Procedures for Toxicology and Clinical Samples

The following methods are used for bioanalysis of samples for 2-weektoxicology studies and clinical samples.

Bioanalysis of samples are performed according to a validated method.Monkey plasma samples are extracted by protein precipitation andanalyzed by UPLC-MSMS using a Waters UPLC and API 5000® triplequadrupole mass spectrometer (AB Sciex, Toronto, Canada) with an ACE®Excel® 2 C18 column (50×3.0 mm, 2 μm particle size). Acquisition andchromatographic peak integration are performed using Analyst® Software1.6.3 (AB Sciex). The peak areas for analytes and internal standard areimported into Watson LIMS® Software version 7.4.1 (Thermo FisherScientific, Philadelphia, USA) for standard curve regression analysisand quantification of analytes in the samples. All analyticalinstruments and software are validated using appropriate procedures.

Example 6 Bioanalysis Procedures for Non-GLP Pharmacokinetic Studies

The following methods are used for bioanalysis of samples for non-GLPpharmacokinetic studies.

Bioanalysis of samples are performed according to a validated method.Plasma samples are extracted by protein precipitation and analyzed byUPLC-MSMS using a Shimadzu UPLC and API 5000® triple quadrupole massspectrometer (AB Sciex, Toronto, Canada), with a Waters Acquity UPLC BEHC18 column (50 mm×2.1 mm, 1.7 μm particle size). Acquisition andchromatographic peak integration are performed using Analyst® Software1.6.3 (AB Sciex). The peak areas for analytes and internal standard areimported into Watson LIMS® Software, version 7.4.1 (Thermo FisherScientific, Philadelphia, USA) for standard curve regression analysisand quantification of analytes in the samples. All analyticalinstruments and software are validated using appropriate procedures.

Example 7 p38 MAPK Substrate Phosphorylation Profile

To assess whether a compound provided by the present disclosureselectively can inhibit phosphorylation consistent with its target. HeLacells are pretreated for 30 min with 10 μM SB203580, 50 μM testcompound, or 0.1% DMSO vehicle control, then with the p38 activator,anisomycin (25 μg/mL) and phosphorylated test compound and Stat-I areanalyzed by immunoblotting.

Example 8 Specific Binding to p38α MAPK

DSF is used to analyze concentration-specific binding of a compound ofFormula (6) to p38α MAPK and p38β APK. To confirm that the test compoundbinds the CADD-targeted pocket, DSF is used to compare compound bindingand SB203580-binding to wild-type p38α MAPK and a p38α MAPK mutant withfour of the ten target pocket amino acids (R49K/HL107-8TF/KI65R)substituted. The mutant can exhibit SB203580-binding that was identicalto wild-type p38α MAPK, but not test compound-binding.

Selective binding of test compound to the CADD-targeted pocket in p38αMAPK is confirmed using Saturation Transfer.

Example 9 Pharmacokinetics

The pharmacokinetics of Compounds (1)-(4) was determined in mice, rats,and monkeys.

Mouse Study.

Female CD-1 mice (n=9) received a single intraperitoneal dose of 1mg/mouse of Compound (4). The dosing formulation was prepared prior todose, with 2 mg/mL of Compound (4) in 4% DMSO and 96% PBS. Blood sampleswere collected from the mice at designated timepoints. Followingcollection, samples were centrifuged (2500 rpm for 10 minutes at 4° C.)and the resulting plasma was recovered and stored frozen (−60° C.).

Bioanalysis of the plasma samples was performed for Compounds (1)-(4).Mouse plasma samples were extracted by protein precipitation andanalyzed by UPLC-MSMS using a Waters UPLC and API 5000® triplequadrupole mass spectrometer (AB Sciex, Toronto, Canada) with a WatersAcquity® UPLC BEH C18 column (50 mm×2.1 mm, 1.7 μm particle size).Acquisition and chromatographic peak integration were performed usingAnalyst® 1.7 Software. The standard curve regression and quantificationof analytes in the samples was performed using the Analyst® Software.

Pharmacokinetic parameters were calculated based on the plasmaconcentration data for Compound (4) and the metabolites Compound (1)-(3)by non-compartmental methods using WinNonlin® Software, version 8.1(Certara®, Inc). The area under the concentration time curve (AUC_(inf))was calculated for Compounds (1)-(4). The percent AUC_(inf) (%AUC_(inf)) for each metabolite was calculated as the ratio of theAUC_(inf) for each respective metabolite divided by the AUC_(inf) forCompound (4).

Rat Study.

Male Sprague-Dawley rats (n=3) received a single intravenous bolus doseof 10 mg/kg Compound (4). The dosing formulation was prepared by priorto dosing, with 5 mg/mL of Compound (4) in 14%sulphobutylether-β-cyclodextrin (SBECD) in deionized water (w/v). Bloodsamples were collected from each rat at designated timepoints. Followingcollection, the samples were centrifuged (2500 rpm for 10 minutes atapproximately 4° C.) and the resulting plasma was recovered and storedfrozen (−60° C.).

Bioanalysis of the samples was performed for Compounds (1)-(4). Ratplasma samples were extracted by protein precipitation and analyzed byUPLC-MSMS using a Waters UPLC and API 5000® triple quadrupole massspectrometer (AB Sciex, Toronto, Canada) with a Waters Acquity® UPLC BEHC18 column (50 mm×2.1 mm, 1.7 μm particle size). Acquisition andchromatographic peak integration were performed using Analyst® 1.7Software. The standard curve regression and quantification of analytesin the samples was performed using the Analyst® Software.

Pharmacokinetic parameters were calculated from the plasma concentrationdata for Compound (4) and the metabolites Compounds (1)-(3) bynon-compartmental methods using WinNonlin® Software, version 8.1(Certara®, Inc). The area under the concentration time curve (AUC_(inf))was calculated for Compounds (1)-(4). The percent AUC_(inf) for themetabolites was calculated as the ratio of the AUC_(inf) for eachrespective metabolite divided by the AUC_(inf) for Compound (4).

Monkey Study:

Male cynomolgus monkeys (n=3) received a single intravenous infusionover a period of 2 hours at a dose of 5 mg/kg Compound (4) (2.5mL/kg/hour). The dosing formulation was prepared prior to dose, with 1mg/mL of Compound (4) in 14% sulphobutylether-β-cyclodextrin (SBECD) indeionized water (w/v). Blood samples were collected from each monkey atdesignated timepoints. Following collection, the samples werecentrifuged (2500 rpm for 10 minutes at 4° C.) and the resulting plasmawas recovered and stored frozen (−60° C.).

Bioanalysis of samples was performed for Compounds (1)-(4). The monkeyplasma samples were extracted by protein precipitation and analyzed byUPLC-MSMS using a Waters UPLC and API 5000® triple quadrupole massspectrometer (AB Sciex, Toronto, Canada) with an ACE® Excel® 2 C18column (50 mm×3.0 mm, 2 um particle size) or a Waters Acquity® UPLC BEHC18 column (50 mm×2.1 mm, 1.7 μm). Acquisition and chromatographic peakintegration were performed using Analyst® Software, version 1.6.3. Thestandard curve regression and quantification of analytes in the sampleswas performed using Watson LIMS® Software, version 7.4.1 (Thermo FisherScientific, Philadelphia, USA) or the Analyst® Software.

Pharmacokinetic parameters were calculated from plasma concentrationdata for Compound (4) and its metabolites by non-compartmental methodsusing WinNonlin® Software, version 8.1 (Certara®, Inc). The area underthe concentration time curve (AUC_(inf)) was calculated for Compounds(1)-(4). The percent AUC_(inf) for each of the metabolites wascalculated as the ratio of the AUC_(inf) of each respective metabolitedivided by the AUC_(inf) of Compound (4).

Following oral administration of compound (2) to a mammal, themetabolites having the structure of Formula (1), (2) or (3) exhibited a% AUC_(inf) (100×AUC_(metabolite)/AUC_(Compound (4))) with respect tocompound (4) as shown in Table 1.

TABLE 1 % AUC of in vivo metabolites of Compound (4). % AUC_(inf)Metabolite Mouse Rat Monkey Compound (1) 31 9 64 Compound (2) 10 48 132Compound (3) 9 11 7

Example 10 Antiviral Effects in a SARS-CoV-2 Infected Cell Line

A549-ACE2 cells (Institut Pasteur, Paris, France) were cultured in DMEM(Corning) supplemented with 10% FBS (Peak Serum) and maintained at 37°C. with 5% CO₂. HEK293T-ACE2 cells (ATCC, CRL-3216) were maintained inDMEM (Corning) supplemented with 10% FB (Peak Serum) andPenicillin/Streptomycin (Corning) at 37° C. and 5% CO₂. hACE2ectopically expressed cells were generated by transducing with alentiviral vector expressing human ACE2. Puromycin resistant cells withhACE2 surface expression were sorted after staining with AlexaFluor647-conjugated goat anti-hACE2 antibodies. Cells were thensingle-cell-cloned and screened for their ability to support SARS-CoV-2replication. All cell lines used were regularly screened for mycoplasmacontamination using a Universal Mycoplasma Detection Kit (ATCC,30-1012K).

The SARS-CoV-2 isolate BetaCoV/France/IDF0372/2020 was supplied by theNational Reference Centre for Respiratory Viruses hosted by InstitutPasteur (Paris, France). The isolate originated from a human sample. Theisolate was supplied through the European Virus Archive goes Global(EVAg) platform. Viral stocks were prepared by propagation in Vero E6cells in DMEM supplemented with 2% FBS. Viral titers were determined byplaque assay in Minimum Essential Media (MEM) supplemented with 2% (v/v)FBS (Invitrogen) and 0.05% agarose.

All experiments involving live SARS-CoV-2 were performed in compliancewith the Institut Pasteur Paris guidelines for Biosafety Level 3 (BSL-3)Containment Procedures in Approved Laboratories.

Two hours before infection, the medium was replaced with DMEM (2% FBS)containing the compound of interest at concentrations 50% greater thanthose indicated, including a DMSO control. Plates were then transferredinto the BSL-3 facility and the same volume of SARS-CoV-2 was added inDMEM (2% FBS), bringing the final compound concentration to the desiredconcentration. Plates were then incubated for 48 hours at 37° C.15% CO₂.All assays were performed in biologically independent triplicates.

Detection of viral genomes was performed by RT-qPCR, directly from theinactivated supernatant. SARS-CoV-2 specific primers targeting the Ngene region: 5′-TAATCAGACAAGGAACTGATTA-3′ (SEQ ID NO: 1) (Forward) and5′-CGAAGGTGTGACTTCCATG-3′ (SEQ ID NO: 2) (Reverse) were used with theLuna® Universal One-Step RT-qPCR Kit (NEB) in an Applied BiosystemsQuantStudio® 7 thermocycler, with the following cycling conditions: 55°C. for 10 minutes, 95° C. for 1 minute, and 40 cycles of 95° C. for 10s, followed by 60° C. for 1 minute. The number of viral genomes isexpressed as PFU equivalents/mL and was calculated by performing astandard curve with RNA derived from a viral stock with a known viraltiter.

Cell viability was measured using the CellTiter® Glo luminescent cellviability assay (Promega) following the manufacturer's instructions, andluminescence measured in a Tecan Infinite® 2000 plate reader.Cytotoxicity was performed in uninfected cells with same compounddilutions and concurrent with viral replication assay. Percent viabilitywas calculated relative to untreated cells (100% viability) and cellslysed with 20% ethanol (0% viability).

A Hill function was fit to each dose response curve using thelsqcurvefit function in MATLAB (R2018a). IC50 (virus) values weredefined as the concentration at which the percent measure (virus or cellviability quantification) crossed the 50% mark. If the fit curve did notbegin above 50% and cross to below 50% throughout the dose response, anIC50 value was marked as greater than the maximum tested concentration.

The cell viability (black) and IC50 (red) curves in a SARS-CoV-2 cellline treated with compounds (4), (1), or (2) is shown in FIGS. 1-3 ,respectively.

Finally, it should be noted that there are alternative ways ofimplementing the embodiments disclosed herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein but maybe modified within the scope and equivalents thereof.

What is claimed is:
 1. A compound having the structure of Formula (6):

or a pharmaceutically acceptable salt thereof, wherein, R¹ is selectedfrom C₁₋₄ alkanediyl, C₁₋₄ heteroalkanediyl, substituted C₁₋₄alkanediyl, and substituted C₁₋₄ heteroalkanediyl; R² is substitutedmorpholin-4-yl; R³ is selected from —C(═O)— and —S(═O)₂—; and R⁴ is—N(R⁵)₂ wherein each R⁵ is independently selected from hydrogen and C₁₋₄alkyl, wherein each substituent is independently selected from —OH, ═O,—NH₂, —NO₂, C₁₋₆ alkyl, C₁₋₆ cycloalkyl, C₆ aryl, C₁₋₆ heteroalkyl, C₁₋₆heterocycloalkyl, and C₅₋₆ heteroaryl.
 2. The compound of claim 1,wherein R¹ is C₁₋₄ alkanediyl.
 3. The compound of claim 1, wherein R² ismono-substituted morpholin-4-yl.
 4. The compound of claim 1, wherein R²is 3-substituted morpholin-4-yl.
 5. The compound of claim 4, whereineach substituent is independently selected from —OH, ═O, and —NH₂. 6.The compound of claim 3, wherein each substituent is ═O.
 7. The compoundof claim 1, wherein R³ is —S(O)₂—.
 8. The compound of claim 1, whereinR⁴ is bonded to the 5-position of the naphthyl moiety.
 9. The compoundof claim 1, wherein, R¹ is methane-diyl; R³ is —S(O)₂—; and R⁴ is—N(R⁵)₂ wherein each R⁵ is independently selected from hydrogen andmethyl.
 10. The compound of claim 9, wherein R² is 3-substituted4-morpholinyl.
 11. The compound of claim 9, wherein in the moiety of R²,the substituent is ═O.
 12. The compound of claim 1, wherein the compoundis selected from:4-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;4-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;4-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;6-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;6-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;and6-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide;or a pharmaceutically acceptable salt of any of the foregoing.
 13. Thecompound of claim 1, wherein the compound is5-amino-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(5) or a pharmaceutically acceptable salt thereof:


14. The compound of claim 1, wherein the compound is5-(methylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(2) or a pharmaceutically acceptable salt thereof:


15. The compound of claim 1, wherein the compound is5-(dimethylamino)-N-(4-((3-oxomorpholino)methyl)phenyl)naphthalene-1-sulfonamide(3) or a pharmaceutically acceptable salt thereof:


16. A pharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof.
 17. A method of treating adisease in a patient comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of the compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein thedisease is treated by inhibiting the p38α MAPK receptor.
 18. A method oftreating a disease in a patient comprising administering to a patient inneed of such treatment a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein the disease is cancer, wherein the cancer is selected frombreast cancer and melanoma.
 19. A method of treating a disease in apatient comprising administering to a patient in need of such treatmenta therapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof, wherein the disease is aninflammatory disease, wherein the inflammatory disease is selected fromacute respiratory distress syndrome, focal segmental glomerulonephritis,atherosclerosis/acute coronary syndrome, chronic obstructive pulmonarydisease, asthma, inflammatory bowel disease, Crohn's disease, psoriasis,lupus, multiple sclerosis, inflammation in hypercholesteremia, pain,diabetes, and rheumatoid arthritis.
 20. A method of treating a diseasein a patient comprising administering to a patient in need of suchtreatment a therapeutically effective amount of the compound of claim 1or a pharmaceutically acceptable salt thereof, wherein the disease is anautoimmune disease, wherein the autoimmune disease is selected fromlupus, graft-versus-host disease, hepatitis C-induced vasculitis, Type Idiabetes, multiple sclerosis, spontaneous loss of pregnancy, an atopicdisease, and an inflammatory bowel disease.
 21. A method of treating adisease in a patient comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of the compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein thedisease is an age-related disease, wherein the age-related disease isselected from hearing loss, muscle degeneration, Werner's syndrome,cellular aging, and Alzheimer's disease.
 22. A method of treating adisease in a patient comprising administering to a patient in need ofsuch treatment a therapeutically effective amount of the compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein thedisease is selected from acute lung injury, acute respiratory distresssyndrome (ARDS), and chronic obstructive pulmonary disease (COPD).